Division of Clinical Biochemistry, Faculty of Medicine of the Philipps University, D-35037 Marburg, Germany
Received 25 March 1999; in revised form 29 July 1999; )
ABSTRACT
Alcohol is a porphyrinogenic agent which may cause disturbances in porphyrin metabolism in healthy persons as well as biochemical and clinical manifestations of acute and chronic hepatic porphyrias. After excessive consumption of alcohol, a temporary, clinically asymptomatic secondary hepatic coproporphyrinuria is observable, which can become persistent in cases of alcohol-induced liver damage. Nowadays, the alcoholliverporphyrinuria syndrome is the first to be mentioned in secondary hepatic disturbances of porphyrin metabolism. Acute hepatic porphyrias (acute intermittent porphyria, variegate porphyria and hereditary coproporphyria) are considered to be molecular regulatory diseases, in contrast to non-acute, chronic hepatic porphyria, clinically appearing as porphyria cutanea tarda (PCT). Porphyrins do not accumulate in the liver in acute porphyrias, whereas in chronic hepatic porphyrias they do. Thus, chronic hepatic porphyria is a porphyrin-accumulation disease, whereas acute hepatic porphyrias are haem-pathway-dysregulation diseases, characterized in general by induction of -aminolevulinic acid synthase in the liver and excessive stimulation of the pathway without storage of porphyrins in the liver. The clinical expression of acute hepatic porphyrias can be triggered by alcohol, because alcohol augments the inducibility of
-aminolevulinic acid synthase. In chronic hepatic porphyrias, however, which are already associated with liver damage, alcohol potentiates the disturbance of the decarboxylation of uro- and heptacarboxyporphyrinogen, which is followed by a hepatic accumulation of uro- and heptacarboxyporphyrin and their sometimes extreme urinary excretion. Especially in persons with a genetic deficiency of uroporphyrinogen decarboxylase, but also in patients with the so-called sporadic variety of PCT, alcohol is able to transform an asymptomatic coproporphyrinuria into PCT. Alcohol has many biochemical and clinical effects on porphyrin and haem synthesis both in humans and laboratory animals. Ethanol suppresses the activity of porphobilinogen synthase (synonym:
-aminolevulinic acid dehydratase), uroporphyrinogen decarboxylase, coproporphyrinogen oxidase and ferrochelatase, whereas it induces the first and rate-limiting enzyme in the pathway,
-aminolevulinic acid synthase and also porphobilinogen deaminase. Therefore, teetotalism is a therapeutically and prophylactically important measure in all types of hepatic porphyrias.
INTRODUCTION
Ethanol should be included in the list of drugs metabolised by hepatic microsomes' (Rubin and Lieber, 1972). Such drugs stimulate their own metabolism, in which haem synthesis is involved, and affect porphyrin synthesis in various ways. Alteration of porphyrin synthesis in an organism without hereditary and acquired toxic disturbances of porphyrin metabolism is an adaptive response. Generally, these adaptive responses caused by alcohol or other drugs in an organism without pre-existent derangements in the haem-biosynthesis sequences do not lead to clinical consequences. But in the genetically determined hereditary disturbance of porphyrin metabolism, alcohol often initiates biochemical and clinical manifestations of the diseases (Doss, 1982
).
The association of haem biosynthesis with ethanol ingestion has been studied since 1935 when Franke and Fikentscher reported that ethanol consumption increases urinary porphyrin excretion, which was found to be approximately doubled after ingestion of 1 l of beer or 90 ml of cognac (Franke and Fikentscher, 1935). Later on, alcohol-mediated coproporphyrinuria was studied by Brugsch (1937), and has been the subject of detailed investigations by several groups ever since (Sutherland and Watson, 1951
; Orten et al., 1963
; Elder, 1976
; McEwin, 1976
; Doss, 1980
; McColl et al., 1980
; Sieg et al., 1991
; Schoenfeld et al., 1996
). Additional research on the interrelationships between alcohol and porphyrin metabolism has been enforced by clinical observations. On the one hand, alcohol consumption, eruption of cutaneous lesions and increase of uroporphyrin excretion are closely correlated (Shanley et al., 1969
; Doss et al., 1971
; Habermann et al., 1975
), whereas, on the other hand, alcohol is recognized as one of the porphyrinogenic drugs for the exacerbation of acute hepatic porphyrias (Goldberg and Rimington, 1962
; Bloomer, 1976
; Wetterberg, 1976
; Eales, 1979
; Moore, 1980
).
Indeed, certain drugs and chemicals, heavy metals and alcohol are known to be significant and frequent factors in the induction and maintenance of subclinical and clinical disturbances of porphyrin metabolism, including hepatic porphyrias (Sieg et al., 1991). Especially acute hepatic porphyrias are triggered by drugs and/or alcohol and have therefore been designated as pharmacogenetic diseases' (Kalow, 1962
). In addition, alcohol is the most frequent manifesting and aggravating factor in chronic hepatic porphyria, including porphyria cutanea tarda.
The clinicalbiochemical interactions between alcohol and porphyrin/haem biosynthesis involve three main aspects: (1) inhibition and stimulation of certain enzymes in the haem-biosynthetic pathway; (2) triggering the biochemical and clinical manifestations of acute and chronic hepatic porphyrias; (3) development of symptomatic disturbances in porphyrin metabolism as secondary coproporphyrinuria and secondary protoporphyrinaemia.
CLASSIFICATION AND DIAGNOSIS OF PORPHYRIAS
The porphyrias are a heterogeneous group of disorders of haem biosynthesis in which specific patterns of overproduc-tion of haem precursors are associated with characteristic clinical features (Nordmann, 1991; Kappas et al., 1995
). The molecular cause of each type of porphyria is the result of a specific decrease in the activity of one of the enzymes of porphyrin and haem biosynthesis and is shown in Table 1
(for an outline of the pathway, see Fig. 1
). Acquired toxic porphyrias, such as acute lead poisoning and the so-called sporadic, non-hereditary or toxic type of chronic hepatic porphyria, are possible under certain conditions, too (Elder, 1976
; Doss, 1982
; Doss et al., 1984
; De Matteis, 1998
).
|
|
Diagnosis of overt porphyria requires metabolic studies. Enzyme tests do not establish that the actual clinical findings are due to an acute or chronic hepatic porphyria. The enzyme deficiency itself is not the factor causing the illness. Decreased enzyme activity reflects only that the patient carries an enzyme mutation. As clinical experience shows, only in a minority of genetically affected family members does the mutation lead to disease expression. In establishing the diagnosis of porphyria under clinical circumstances, one has to start with metabolite studies (Hindmarsh, 1998). Thus, diagnosis and differential diagnosis of clinically manifest porphyrias can be made by the measurements of porphyrins and their precursors that are excreted into urine or faeces or that are elevated in erythrocytes (Table 1
).
For the acute porphyrias there is little doubt that, in the future, DNA analysis will be the method of choice to detect presymptomatic carriers, and consequently to improve the prevention of the acute clinical expression of these porphyrias.
GENETICS OF PORPHYRIAS
During recent years, cDNA clones have been obtained for the enzymes of haem biosynthesis and the structures of the corresponding genes have been determined. These advances are transforming our knowledge of haem biosynthesis and are certain to improve both our understanding of the pathogenesis of the porphyrias and the methods for identification of carriers of the genes for these disorders (Elder and Nordmann, 1990; Nordmann et al., 1990
). The enzymes of the biosynthetic pathway have all been mapped to specific chromosomes (Table 2
). The molecular nature of the enzymatic defect is highly heterogeneous, and multiple defects have been demonstrated in each porphyria.
|
Porphyria variegata.
The complete genomic sequence of the protoporphyrinogen oxidase gene has been reported (Puy et al., 1996). Mutations in this gene have been shown in South African and French patients with variegate porphyria (Deybach et al., 1996
; Warnich et al., 1996
).
Hereditary coproporphyria.
The sequence and the organization of the gene for the coproporphyrinogen oxidase have been elucidated. It is a 14-kilobase gene with seven exons and six introns (Grandchamp et al., 1995). To date, 14 mutations in the heterozygous case of the coproporphyrinogen oxidase gene have been described (Delfau-Larue et al., 1994
; Fujita et al., 1994
; Martasek et al., 1994
; Lamoril et al., 1995
, 1997
; Schreiber et al., 1997
; Susa et al., 1998
; Doss et al., 1999
).
-Aminolevulinic acid dehydratase defect porphyria.
This porphyria is inherited in an autosomal recessive way (Doss et al., 1986
). Cloning and sequencing of the mutated genes of one patient showed two different point mutations at each allele of the
-aminolevulinic acid dehydratase gene. The expression of one mutation resulted in a nearly inactive enzyme. The other gene defect produced an unstable protein (Ishida et al., 1992
).
Chronic hepatic porphyria
Porphyria cutanea tarda (PCT).
The clinical cutaneous stage of chronic hepatic porphyria is PCT. PCT is characterized by a chronic hepatic porphyria disease process. The term PCT is used to indicate a heterogeneous group of diseases, all characterized biochemically by inhibition of liver uroporphyrinogen decarboxylase and consequent accumulation of uroporphyrin and other highly carboxylated porphyrins; and clinically, by cutaneous symptoms of photosensitivity often associated with evidence of liver damage. Most patients have sporadic (type I) PCT, where decreased uroporphyrinogen decarboxylase activity is restricted to the liver, and a familial occurrence is not observed (Table 3). The liver-specific enzyme defect does not appear to be caused by mutation at the uroporphyrinogen decarboxylase locus (Elder, 1998
). However, some cases of PCT that are biochemically indistinguishable from the type I form are clustered in families. At present, it is unclear whether these cases, known as type III PCT, represent a distinct form of the disease or indicate a strong inherited contribution, presumably from outside the uroporphyrinogen decarboxylase locus, to the pathogenesis of type I PCT (Elder, 1998
). Table 3
also shows that ~2050% of patients have familial (type II) PCT, in which the uroporphyrinogen decarboxylase enzyme deficiency is present in all tissues and inherited in an autosomal dominant pattern (Held et al., 1989
; Doss et al., 1991
; Elder, 1998
). Clinical penetrance is low, with <10% of affected individuals developing symptoms. Both catalytic activity and concentration of the immunoreactive enzyme are half normal in erythrocytes, indicating near to total absence of protein product from the mutant allele. This type of PCT is related to the rare disorder hepatoerythropoietic porphyria, where uroporphyrinogen decarboxylase activity is decreased by
75% in all tissues, and sustained overproduction of porphyrins is associated with onset during early childhood of skin lesions that are usually severe and persistent (Elder, 1998
).
|
Erythropoietic porphyria
Erythropoietic protoporphyria.
Erythropoietic protoporphyria is associated with a partial deficiency of ferrochelatase activity. In most cases, it is inherited in an autosomal dominant fashion with a variable degree of penetrance. A de-novo mutation, two deletions and two point mutations were detected in Finnish erythropoietic protoporphyria families (Henriksson et al., 1996). A family with autosomal dominant erythropoietic protoporphyria and coinheritance of a low output normal ferrochelatase allele and a mutant allele has been reported from the French porphyria centre (Gouya et al., 1996
), suggesting a more complex mode of inheritance. Recently it has been shown that coinheritance of a ferrochelatase gene defect and a wild-type low expressed allele is generally involved in the clinical expression of erythropoietic protoporphyria (Gouya et al., 1999
). A compound heterozygous, autosomal recessive form of erythropoietic protoporphyria has been reported (Sarkany et al., 1994
). This form of protoporphyria is characterized by severe photosensitivity and cholestatic liver disease in adolescence (Sarkany and Cox, 1995
).
Congenital erythropoietic porphyria.
Congenital erythro-poietic porphyria is a rare autosomal recessive disorder of porphyrin metabolism, which can be homozygous or compound heterozygous at the molecular level (Kappas et al., 1995). The uroporphyrinogen III synthase enzyme deficiency leads to an excessive production, accumulation and excretion of predominantly type I porphyrins, which clinically induce severe cutaneous photodermatosis, mostly in association with a haemolytic process (Freesemann et al., 1998
). In recent papers, a progress in gene therapy in congenital erythropoietic porphyria is discussed. French authors have been successful in repairing the mutation of the uroporphyrinogen III synthase in bone marrow cells by retroviral vectors (Mazurier et al., 1997
).
A mutagenic effect of alcohol on the enzymes of haem biosynthesis is unknown. The action of alcohol on porphyrin biosynthesis is due to an induction and inhibition of several enzymes. The consequence may be a clinical porphyria process with an acute manifestation in the case of a genetic disposition.
SECONDARY PORPHYRINOPATHIES
The disturbances of porphyrin metabolism are principally differentiated into porphyrias and secondary porphyrinopathies, that is, porphyrinurias and porphyrinaemias (Doss, 1987). Such secondary porphyrinurias are generally confined to excessive urinary coproporphyrin without uroporphyrinuria,
-aminolevulinic aciduria, or porphobilinogenuria, and secondary porphyrinaemias to excessive zinc-protoporphyrin concentration in erythrocytes (Doss, 1987
).
Secondary coproporphyrinuria is the most frequent secondary hepatic disturbance of porphyrin metabolism (Doss and Groß, 1997). A reasonable definition and description of porphyrinuria was proposed by Goldberg and Rimington (1962) as follows: In the past the term porphyria was reserved for those diseases of porphyrin metabolism caused by an inborn error of metabolism, that is, a genetic defect. The term porphyrinuria should be confined to those minor disorders of porphyrin metabolism caused by another disease, or certain drugs or chemicals, in which the clinical features are not directly attributable to the porphyrin abnormality.
Thus, secondary coproporphyrinuria means that an increased excretion of coproporphyrin occurs as the biochemically dominant symptom of a disturbance in porphyrin and haem metabolism during an intoxication, individual condition, or basic disease (Table 4). Secondary coproporphyrinuria is observed in two-thirds of patients with hepatic damage, especially alcoholic liver disease. The alcoholliver porphyrinuria syndrome is the first to be mentioned in secondary hepatic disturbances of porphyrin metabolism (Doss and Sieg, 1995
).
|
THE INFLUENCE OF ALCOHOL ON ENZYMES OF HAEM BIOSYNTHESIS
The metabolic effect of alcohol on enzymes of haem biosynthesis is very complex (Fig. 1) and has been the subject of numerous studies over many years. In this section, clinical and experimental studies on the influence of alcohol on enzymes in hepatic and non-hepatic tissues will be reviewed.
-Aminolevulinic acid synthase
-Aminolevulinic acid synthase (ALAS) is the first and rate-limiting enzyme in the haem biosynthetic pathway. It catalyses the condensation of glycine and succinyl CoA to form
-aminolevulinic acid. There are two tissue-specific isoenzymes, i.e. the non-specific isoform (ALAS-N) expressed ubiquitously and the erythroid-specific isoform (ALAS-E) expressed exclusively in erythroid cells (Doss and Sassa, 1994
; Kappas et al., 1995
; Harigae et al., 1998
). The human ALAS-N gene has been assigned to chromosome 3p21, the ALAS-E gene to a distal subregion of band X p11.2 (Harigae et al., 1998
). Biosynthesis of haem in the liver is controlled largely by the production rate of the hepatic isoform of
-aminolevulinic acid synthase. The activity of this enzyme is rate-limiting, and enzyme synthesis is feedback-regulated by the intracellular concentration of haem. In contrast, the regulation of haem synthesis in erythroid cells is not controlled by the erythroid-specific
-aminolevulinic acid synthase isoform alone.
In accord with the differing control of erythroid-specific -aminolevulinic acid synthase and the hepatic isoform of
-aminolevulinic acid synthase, iron-responsive elements (IRE) have been identified on the mRNA for the erythroid-specific
-aminolevulinic acid synthase. This IRE phenomenon is probably functional, and it implies that the IRE and the IRE-binding protein system is involved in the control of haem biosynthesis during erythroid differentiation (Cox et al., 1991
; Dandekar et al., 1991
).
Studies in animals and cell cultures.
The effect of alcohol on the hepatic -aminolevulinic acid synthase on both animals and cell cultures has been studied over many years. Shanley et al. (1968), Beattie et al. (1973), Moore (1974) and Held (1977) reported that ethanol is a well known porphyrinogen, and it is induced by ~3-fold hepatic
-aminolevulinic acid synthase activity in laboratory animals as well as in cultured rat hepatocytes (Lane and Stewart, 1983
). Held (1977) showed that after acute alcohol ingestion (a single dose of 2 g alcohol/kg body weight) the activity of
-aminolevulinic acid synthase in the liver of starved rats increased 23-fold within 3 h, and by ~4-fold after chronic alcohol consumption (drinking an 8% alcohol solution instead of water for 1621 and 56 days). Consequently, porphyrin synthesis was stimulated. A previous injection of pyrazole could abolish the inducing effect of alcohol on the
-aminolevulinic acid synthase. The inducing effect of alcohol was increased by a previous injection of phenobarbital (Held, 1977
). The activity of hepatic
-aminolevulinic acid dehydratase, the concentration of cytochrome P-450 and the activity of the microsomal monoxygenase were not altered in these animals (Held, 1977
), in contrast to a decrease in hepatocytes, where ethanol treatment also caused a transient decrease in intracellular haem (Lane and Stewart, 1983
). Teschke et al. (1987) studied the effect of prolonged alcohol consumption on hepatic haem and porphyrin metabolism. Female Wistar rats were fed for 60 days a nutritionally adequate liquid diet containing 36% of total calories as ethanol, whereas the control diet was isocaloric and contained no alcohol. The administration of the alcohol diet resulted in an increased hepatic activity of
-aminolevulinic acid synthase by 223% (112.3 ± 19.6 versus 362.8 ± 42.5 nmol/h/100 g body weight; P < 0.01), an enhanced urinary excretion of
-aminolevulinic acid by 101% (64.8 ± 11.8 versus 130.8 ± 22.4 nmol/day; P < 0.05), and an augmented urinary output of total porphyrins by 142% (1.2 ± 0.2 versus 2.9 ± 0.5 nmol/day; P < 0.05). Concomitantly, the hepatic content of cytochrome P-450 was significantly enhanced and that of hepatic catalase activity marginally increased.
The mechanisms by which ethanol induces the activity of -aminolevulinic acid synthase are not yet completely elucidated. Different possibilities were discussed. (1)
-Aminolevulinic acid synthase is under negative feedback control by free haem, and the increased activity of this enzyme may indicate reduced intra-mitochondrial concentrations of free haem as a result of either reduced synthesis or increased utilization. (2) The alcohol-related depression of the intermediate enzymes in the pathway might reduce haem synthesis. (3) Increased haem requirement in the liver cells may occur as ethanol enhances the synthesis of the haemoprotein cytochrome P-450 (Pennington et al., 1978
; Teschke et al., 1987
). (4) The porphyrinogenic effect of ethanol may not be caused by alcohol itself, but either by its metabolites acetaldehyde or acetate or by changes of the liver metabolism caused by the effect of alcohol on the redox state of the NAD couple (Shanley et al., 1968
; Labbe et al., 1970
; Beattie et al., 1973
; Held, 1977
), because the hepatic metabolism of ethanol alters the intra-mitochondrial redox state.
Studies in humans.
The effect of alcohol on hepatic -aminolevulinic acid synthase in humans is comparable to that in animals. In the study of Shanley et al. (1969), evidence was presented that, when patients with symptomatic porphyria were challenged with alcohol, liver
-aminolevulinic acid synthase activity is raised, leading to increased urinary porphyrin excretion. Conversely, enforced abstinence from alcohol may induce remission of various degrees. An increased hepatic
-aminolevulinic acid synthase activity was also observed in cirrhotic patients (Bonkowsky and Pomeroy, 1977
; Kodama et al., 1983
). But this increase does not seem to reach levels expected in acute intermittent porphyria and is not followed by an elevation of urinary
-aminolevulinic acid and porphobilinogen excretion, in contrast to acute hepatic porphyrias (Doss et al., 1972
; Bonkowsky and Pomeroy, 1977
).
The effect of alcohol on -aminolevulinic acid synthase in humans is not confined to hepatic tissue. Brodie et al. (1979) and McColl et al. (1980, 1981) monitored the effects of acute and chronic ethanol ingestion on the activities of the enzymes of haem biosynthesis in peripheral blood cells. Their results demonstrated that ethanol consumption causes an increased activity of leukocyte
-aminolevulinic acid synthase after acute (McColl et al., 1980
) as well as chronic (Brodie et al., 1979
; McColl et al., 1981
) ethanol ingestion. In addition, McColl et al. (1980, 1981) investigated the changes in the activity of
-aminolevulinic acid synthase in leukocytes after acute alcohol ingestion in healthy subjects as well as in chronic alcoholics. In healthy non-porphyric subjects, the ingestion of 200 ml of 69.5% vodka (1 x 316 mol ethanol) raised the activity of leukocyte
-aminolevulinic acid synthase on average by 110% (McColl et al., 1980
) and similar disturbances of haem biosynthesis were observed in chronic alcoholics (McColl et al., 1981
).
In the acute reversible sideroblastic anaemia of alcoholics, increased bone marrow -aminolevulinic acid synthase activity was noted (Fraser and Schacter, 1980
). In contrast, patients with sideroblastic anaemia showed diminished
-aminolevulinic acid synthase activity (Bottomley et al., 1973
).
The mechanisms by which ethanol induces the activity of -aminolevulinic acid synthase in humans are similar to those discussed in animal and cell culture studies.
-Aminolevulinic acid dehydratase
Among those enzymes of porphyrin metabolism which are affected by alcohol, -aminolevulinic acid dehydratase is the second in the haem-biosynthetic pathway and catalyses the condensation of two
-aminolevulinic acid molecules to porphobilinogen, the immediate precursor of porphyrinogens. Biochemically, this enzyme consists of eight identical subunits and contains sulphydryl groups and zinc, which are essential for its full activity (Shemin, 1976
; Anderson and Desnick, 1979
; Sieg et al., 1991
).
Studies in animals and cell cultures.
Regarding the effect of alcohol on -aminolevulinic acid dehydratase activity in the rat, Moore et al. (1971) showed that the maximum alcohol concentration in the blood, reached within 2 h of alcohol intake, corresponded to a decrease in
-aminolevulinic acid dehydratase activity. The effect of ethanol intoxication on
-aminolevulinic acid dehydratase activity has also been measured in other tissues. A significant depression of enzyme activity in blood, liver and kidney, but not in heart or spleen, was shown by Moore et al. (1971). These authors concluded that effects of ethanol on
-aminolevulinic acid dehydratase will be localized to those organs known to metabolize or handle ethanol, since it is only in those organs that the NAD redox potential will be sufficiently elevated to repress
-aminolevulinic acid dehydratase activity. These observations confirm the data reported by Abdulla et al. (1976), where a considerable decrease in the activity of the liver enzyme in rats after ethanol loading was recognized.
Studies in humans.
In humans, the effect of alcohol has been well studied for -aminolevulinic acid dehydratase, where acute ingestion of alcohol has a marked and direct effect on its activity. It was first shown by Moore et al. (1971) that the
-aminolevulinic acid dehydratase activity was depressed by ethanol in human blood cells; an effect closely related to the increase in blood alcohol concentration. A more differentiated investigation by Sieg et al. (1991) showed differences in the response of this enzyme after cessation of alcohol consumption in normal subjects compared to chronic exposure in alcoholics. Following the administration of alcohol to a group of six normal subjects,
-aminolevulinic acid dehydratase activity was diminished by 44%.
-Aminolevulinic acid dehydratase activity in a group of alcoholic subjects was found to be even more strongly inhibited, by 57% on average. These findings are in agreement with experiments in vivo by other authors (Krasner et al., 1974
; McColl et al., 1980
, 1981
; Kondo et al., 1983
; Doss, 1985
).
An increase of the intracellular NAD redox potential by alcohol and its effects on the redox balance of other compounds within the cell has been regarded as a direct cause of the enzyme inhibition. The augmented redox potential may influence the equilibrium between oxidized and reduced forms of sulphydryl compounds (Moore et al., 1971; Sieg et al., 1991
). On the other hand, the toxicity of acetaldehyde (interaction with amino acids and binding to cystein and/or glutathione) may decrease glutathione concentration in the liver (Lieber, 1980
; Sieg et al., 1991
). Glutathione depletion may contribute to the change in
-aminolevulinic acid dehydratase activity. In addition, it may promote peroxidative damage of cellular membranes, which is one pathogenetic factor for the chronic hepatic porphyria (Koszo et al., 1982
).
More than 20 years ago, Abdulla et al. (1976) reported that the induction of -aminolevulinic dehydratase by zinc counteracts the inhibitory effect of orally administered ethanol in rats. Later on, in vitro assays on human erythrocytes after acute and chronic alcohol ingestion in vivo showed that reactivation by dithiothreitol was better than that by zinc ions. The most potent effect on restoration of
-aminolevulinic dehydratase activity occurred under the combined addition of zinc and dithiothreitol (Sieg et al., 1991
). The easily performed reactivation of this enzyme in vitro is an additional help in recognizing and excluding irreversible inhibitory effects, such as those caused by styrene (Fujita et al., 1987
) or hereditary enzyme deficiency (Doss et al., 1984
; Sieg et al., 1991
). Additionally, the extent of lead intoxication, which also induces a reversible
-aminolevulinic dehydratase inhibition, may be diagnosed (Polo et al., 1995
).
Erythrocyte -aminolevulinic dehydratase activity was also assessed for outpatient detection of alcoholic liver disease and compared with
-glutamyltransferase and casual blood ethanol (Hamlyn et al., 1979
). These authors found that the highest specificity for alcoholism was achieved by
-aminolevulinic dehydratase; the best overall performance, with highest sensitivity and specificity, was, however,
-glutamyltransferase. Erythrocyte
-aminolevulinate dehydratase activity may also be regarded as a sensitive biochemical indicator for chronic alcohol consumption, as has been proposed by Krasner et al. (1974), and also for acute alcohol intake (Sieg et al., 1991
). This suggestion differed from the result reported by Aubin et al. (1997), where
-aminolevulinic dehydratase showed no advantage over
-glutamyltransferase as a marker for recent alcohol intake.
The effect of alcohol on -aminolevulinic dehydratase activity in the liver has not been studied so far. However, there is evidence for a similar reaction of liver and erythrocyte
-aminolevulinic dehydratase after alcohol uptake (Sieg et al., 1991
).
Porphobilinogen deaminase
Studies in humans
Acute alcohol ingestion in healthy subjects results in an increased activity of porphobilinogen deaminase in erythrocytes (McColl et al., 1980). An increased activity was also observed in chronic alcoholics (McColl et al., 1981
). More recently, the activity of porphobilinogen deaminase in erythrocytes of alcoholics was assayed and compared to those in controls and abstaining alcoholics (Wright et al., 1990
). Confirming the results obtained by McColl et al. (1981), the porphobilinogen deaminase activity in alcoholics was found to be significantly higher than that of controls and significant correlations between enzyme activity and mean corpuscular volume (MCV) could also be observed. Alcoholics abstaining from alcohol over a 9-month period showed a return to normal enzyme activity paralleling the normalization of their MCV (Wright et al., 1990
).
It is not known if the results obtained in peripheral blood cells are applicable to the liver and consequently have impact on the regulatory disturbance in porphyria gene carriers and patients.
Uroporphyrinogen decarboxylase
Studies in animals and humans.
Uroporphyrinogen decarboxylase is reduced in experimental chronic hepatic porphyria (Elder et al., 1976; von Tiepermann et al., 1980
) and in human chronic hepatic porphyria, clinically appearing as PCT (Doss et al., 1980
; Doss, 1982
, Doss and Sassa, 1994
). In order to find out if alcohol can be the exogenous toxic cause of chronic hepatic porphyria, via an inhibition of uroporphyrinogen decarboxylase, Doss et al. (1980, 1981) examined the influence of alcohol consumption on the enzyme activity in hepatic and non-hepatic tissues of female SpragueDawley rats. Chronic alcohol intake inhibited uroporphyrinogen decarboxylase activity in liver and spleen, associated with a pathological porphyrinuria (Doss et al., 1980
, 1981
). McColl et al. (1980, 1981) showed that, in humans, acute and chronic alcohol consumption inhibits uroporphyrinogen decarboxylase activity in erythrocytes.
Alcohol is an important manifestation factor in all types of PCT (see Table 3). One can assume that persons processing the genetic variant of uroporphyrinogen decarboxylase deficiency may be more sensitive (Doss, 1985
; Hift and Kirsch, 1995
). Alcohol omission leads to a decline in porphyrin excretion (Topi et al., 1984
).
The mechanisms whereby alcohol and other causes of hepatocyte damage, such as hepatitis C (HCV) infection and oestrogens, provoke PCT in susceptible individuals have not been established. Recent studies show that hepatotoxins such as alcohol, HCV and other infections may release stored iron from ferritin in a form that catalyses the formation of reactive oxygen species and thus switch on the inactivation. Iron inhibits uroporphyrinogen decarboxylase: (a) by direct interaction with the essential sulphydryl groups of the enzyme; (b) indirectly, due to generation of free radicals in the presence of oxygen and an electron donor such as cysteine (Mukerji et al., 1984; Hift and Kirsch, 1995
; Elder, 1998
). These radicals might interact directly with the enzyme and/or oxidize the porphyrinogen substrates to non-metabolizable porphyrins, which accumulate in porphyric patients (Mukerji et al., 1984
, 1997
; De Matteis, 1998
).
Coproporphyrinogen oxidase
Studies in humans and animals.
Coproporphyrinogen oxidase is the sixth enzyme of the haem-biosynthetic pathway. This soluble protein is localized in the intermembrane space of mitochondria and catalyses the conversion of two propionate groups at positions 2 and 4 of coproporphyrinogen III to two vinyl groups of protoporphyrinogen IX (Doss and Sassa, 1994; Martasek et al., 1994
). The effects of chronic and acute ethanol treatments on the enzyme seem to be different, as the coproporphyrinogen oxidase activities in leukocytes were found unchanged in chronic alcoholics (McColl et al., 1981
) and depressed in healthy humans after acute ethanol ingestion (McColl et al., 1980
). In a study performed by Li et al. (1989) the specific and total activity of coproporphyrinogen oxidase have been assayed in human liver from healthy control subjects and patients with alcoholic liver disease. Statistical analysis showed no significant differences in enzyme specific activity or total activity between the chronic alcoholics with fatty liver and control subjects. Later, Li et al. (1990) studied the influence of alcohol on coproporphyrinogen oxidase in chronically and acutely ethanol-treated rats. In contrast to the results reported by McColl et al. (1980), both chronic ethanol feeding and acute ethanol injection (fasting or non-fasting) showed no effects on the activity of coproporphyrinogen oxidase.
It seems probable that the molecular injury to mitochondria produced by ethanol and acetaldehyde changes the activity of this hepatic enzyme, resulting in a pathological coproporphyrinuria; alcohol interferes with functions of the inner mitochondrial membrane (Cederbaum and Rubin, 1975). The change in the redox state of the cell with an increase in the hepatic [NADH]/[NAD+] ratio therefore cannot serve as an explanation of coproporphyrinuria, as NAD+ is not a cofactor of mammalian coproporphyrinogen oxidase (Doss, 1985
). On the other hand, coproporphyrinogen oxidase is highly sensitive to changes in oxygen concentrations (Keithly and Nudler, 1983
). Factors affecting the metabolism of coproporphyrinogen III are intriguing (Elder, 1976
): a decrease in the amount of the active enzyme as well as competitive inhibition has been discussed in connection with an increased oxidation and decreased uptake of coproporphyrinogen by the inner membrane of the mitochondrion.
Protoporphyrinogen oxidase
Protoporphyrinogen oxidase activity in both acutely and chronically ethanol-treated rats was not significantly different from controls (Li et al., 1990). Also, in patients with alcoholic fatty liver the specific and total activities of protoporphyrinogen oxidase in the liver seem to be unchanged (Li et al., 1989
).
Ferrochelatase
Studies in animals and cell cultures.
Ferrochelatase, the enzyme that inserts iron into protoporphyrin to form haem, shows a marked depression after administration of ethanol. Decreased ferrochelatase activity was found in acutely ethanol-dosed rats (Moore, 1974, 1998
; Moore et al., 1984
). In chronically ethanol-fed rats normal ferrochelatase activity was found (Li et al., 1990
). The activity in acutely ethanol-treated rats was not measured in the last-named study.
Studies in humans.
A significant suppression of leukocyte ferrochelatase activity in healthy humans after acute ethanol ingestion was reported by McColl et al. (1980). A depression of the activity of ferrochelatase was also found in hepatic tissue. In chronic alcoholics, however, ferrochelatase was reported normal (McColl et al., 1981). This agrees with the results reported by Li et al. (1989) that show that, in chronic alcoholic patients who consumed between 80 and 180 g of ethanol per day, the ferrochelatase activity was not significantly different from controls.
ALCOHOL AS INDUCING FACTOR OF HEREDITARY PORPHYRIAS
Toxic strains on the organism caused by certain chemicals, heavy metals, drugs or alcohol affect the haem pathway functionally. The extent of the toxic effect on porphyrin and haem biosynthesis in the liver depends not only on the quantity and duration of the precipitating factor but also on the type of cell that is influenced (a healthy cell, one that is already damaged by other processes or a cell with hereditary enzyme defects of haem biosynthesis). Since alcohol affects haem biosynthesis even in healthy organisms, its effect on an already genetically damaged synthesis must be stronger than on intact control mechanisms of the molecular feedback of haem/ -aminolevulinic acid synthase in the liver (Goldberg et al., 1981
). In the following sections, the influence of alcohol on the clinical manifestation of the porphyrias based on hereditary defects of porphyrin metabolism will be described.
Acute hepatic porphyrias
Acute hepatic porphyrias are regulatory diseases' with pharmacogenetic implications due to the enhanced inducibility of -aminolevulinic acid synthase (Doss, 1982
). A variety of factors may precipitate the clinical attacks in patients with the genetic defect in each of the acute porphyrias. The most important precipitating factors are drugs, hormones, calorie-reduced diet and alcohol (Nordmann, 1991
; Doss and Sassa, 1994
; Groß et al., 1995
; Kappas et al., 1995
; Moore, 1998
). In our previous aetiological study of 100 patients with acute hepatic porphyrias, alcohol was in second position as a causative factor (16%). Drugs, including oestrogens, were responsible for about half of the clinical exacerbations. Fasting together with alcohol led to manifestations of the acute phase in 5% of the cases.
In the biochemical and clinical manifestation of hepatic porphyrias from disorder to disease triggered by alcohol, four phases can be differentiated (Table 5). A single consumption of alcohol (>80 g) or chronic alcohol abuse may shift acute hepatic porphyrias from the compensated latent phase into the decompensated latent phase (with remarkable increase of porphyrin precursor and porphyrin excretion without overt disease) and from the decompensated latent phase into the clinically manifest stage with abdominal, neurological, cardiovascular and psychiatric syndromes. Doss et al. (1982) reported that patients in the decompensated latent phase with high excretory profiles of haem precursors are especially endangered. Alcohol intake of >60 g/day can increase urinary
-aminolevulinic acid, porphobilinogen, and porphyrin excretion up to 36-fold (Table 6
), leading to an acute exacerbation (Doss et al., 1982
). Recently, a patient was reported suffering from
-aminolevulinic acid dehydratase deficiency in the acute crisis that was associated with an excessive intake of alcohol (300 g in one day). Urinary excretion of
-aminolevulinic acid, porphobilinogen, and total porphyrins have been 2.6 mmol, 29 and 10.7 µmol per day, respectively (Groß et al., 1998
).
|
|
Alcohol increases the absorption of drugs like phenobarbital and inhibits the rates of disappearance of the porphyrinogenic drugs phenobarbital, tolbutamide and meprobamate in vivo in man and animals (Mezey, 1976). Inhibition of drug metabolism results from direct interference with alcohol. Acceleration of drug metabolism is due to the induction of microsomal enzymes by ethanol and can increase toxicity (Mezey, 1976
). Both actions provide a synergistic basis for the expression of acute porphyrias as a pharmacogenetic disease. Alcohol increases the induction of
-aminolevulinic acid synthase in rats pre-treated with phenobarbital (Held, 1977
). A sensitization of hepatic haem biosynthesis by the drug to the porphyrinogenic effect of alcohol is suggested. Drugs potentiate the porphyrinogenic effect of alcohol and vice versa in patients with the genetic enzyme defects of acute hepatic porphyria.
Porphyria cutanea tarda
Porphyria cutanea tarda is the most frequent porphyria, and is regularly associated with liver lesions such as fatty liver, chronic hepatitis, fibrosis, cirrhosis or siderosis (Lefkowitch and Grossmann, 1983; Cripps, 1987
; Köstler and Doss, 1993
; Freesemann et al., 1995
). The disease-promoting site of the pathological porphyrin metabolism is the liver, therefore PCT is described as chronic hepatic porphyria (Doss, 1990
). Hepatic uroporphyrinogen decarboxylase activity is decreased in all patients, however the activity of this enzyme in blood cells and in other tissues is decreased only in the genetically determined type (Doss et al., 1980
). Skin symptoms characterize the biochemically and clinically manifest stage. Latent or subclinical phases in which urinary porphyrin constellations change from mild to severe stages can be recognized before cutaneous lesions arise. The development of chronic hepatic porphyria is outlined in Figure 2
. In a course of gene environment interaction (alcohol, oestrogens and hormonal contraceptives, polyhalogenated organocompounds etc.), the chronic hepatic porphyria disease process is initiated (Doss et al., 1991
). Alcohol is the factor most commonly associated with the development of porphyria cutanea tarda in humans (Habermann et al., 1975
; Grossmann et al., 1979
; Hift and Kirsch, 1995
; De Matteis, 1998
). According to our own investigations, alcohol was the causative factor in about two-thirds of the cases (Doss, 1982
). Alcohol consumption correlates positively with total porphyrin excretion and with the excretion of urocarboxyporphyrin and heptacarboxyporphyrin (Doss et al., 1971
). The strong association of alcohol with PCT could be explained by the inhibiting effect alcohol has on uroporphyrinogen decarboxylase and by inducing
-aminolevulinic acid synthase (Doss, 1985
; Hift and Kirsch, 1995
). However, recent studies show that its contribution to the development of PCT may be indirect, perhaps by precipitating PCT by an iron-dependent mechanism (Hift and Kirsch, 1995
; De Matteis, 1998
).
|
Additional exacerbating or precipitating factors that have been identified more recently and which appear to play a dominant role in most cases of sporadic PCT are viral infections. Among these, the first viral infection found to be associated with PCT was the one caused by hepatitis B virus (HBV) (Bel and Girard, 1980). A similar effect of human immunodeficiency virus infection has been reported by Wissel et al. (1987), Lobato and Berger (1988), Blauvelt et al. (1992) and Soriano et al. (1993). However, the viral infection that is described most frequently in connection with PCT is the HCV. Approximately 6090% of patients from Italy, Spain, and France who had PCT were HCV-seropositive (Fargion et al., 1992
; Ferri et al., 1993
; Lacour et al., 1993
; Cribier et al., 1995
; Navas et al., 1995
; Blauvelt, 1996
; Martinez et al., 1996
; Quecedo et al., 1996
). However, studies in Germany (Stölzel et al., 1995
) and New Zealand (Salmon, 1996
) showed less correlation between positive anti-HCV antibodies and PCT than those in southern European countries.
Erythropoietic (hepatic) protoporphyria
Hepatobiliary complications in erythropoietic protoporphyria are not caused by alcohol, but more likely by a toxic effect of protoporphyrin deposited in the liver and the bile duct system (Bloomer, 1982). As alcohol also inhibits hepatic ferrochelatase which is genetically defective in this disease, and produces liver damage its ingestion presents a pathogenetic factor for the expression and/or aggravation of the potential hepatobiliary involvement.
ALCOHOL AND SECONDARY HEPATIC COPROPORPHYRINURIA
The relation between coproporphyrinuria, alcohol and alcoholic liver disease has been known for a long time (Brugsch, 1937; Orten et al., 1963
; Doss et al., 1972
; Ostrowski et al., 1984
). More recently Sieg et al. (1991) and Schoenfeld et al. (1996) measured the increase in renal coproporphyrin excretion after alcohol intake by healthy patients, as well as in alcoholics with and without liver defects. In the study of Sieg et al. (1991), determination of urinary
-aminolevulinic acid, porphobilinogen and coproporphyrin showed increased levels for all non-alcoholics after acute alcohol ingestion (160 230 g/4 h alcohol). Among the group of chronic alcoholics,
-aminolevulinic acid and porphobilinogen excretion remain within the normal range, although the values for coproporphyrin were found to be distinctly or even strongly increased. The study by Schoenfeld et al. (1996), on the influence of alcohol on patients with and without liver damage, showed that the extent of the coproporphyrinuria in alcoholics increases with the severity of liver damage. This study also measured the distribution of coproporphyrin isomers I and III in the urine of the participants. Healthy patients showed a preponderance of coproporphyrin isomer III, whereas alcoholics excrete more coproporphyrin isomer I. Among alcoholics with no evidence of hepatocellular damage, the proportion of coproporphyrin isomer I was 55%; in alcoholics with moderate (i.e. fatty liver and impaired function of liver enzymes) and severe liver disease (i.e. liver cirrhosis), this proportion was 80%. The increased coproporphyrin excretion in all three groups (healthy patients and alcoholics with and without liver damage) demonstrates the effect of alcohol on haem metabolism. But the difference in the distribution of coproporphyrin isomers I and III, as well as in the excretion of the porphyrin precursors (
-aminolevulinic acid and porphobilinogen) enabled us to differentiate between the direct primary effect of alcohol on the haem-biosynthetic pathway and the secondary indirect effect, which is probably related to liver damage that follows alcohol consumption (Doss, 1987
). Thus, coproporphyrinuria in patients without liver damage after acute alcohol ingestion is mainly due to a direct inhibition of coproporphyrinogen oxidase in the liver counter-regulated by an increase of
-aminolevulinic acid synthase. On the other hand, the coproporphyrinuria observed in chronic alcoholic liver disease is due to the secondary effect of alcohol. In this case an impairment in the postulated common hepatic carrier transport mechanism caused a reduction in total coproporphyrin transport into bile with consequent diversion of more of the type I than type III isomer compound from biliary to the urinary route of elimination (Kaplowitz et al., 1972
; Doss, 1987
). Therefore, excessive coproporphyrin isomer I in the urine is a useful sign of acquired intrahepatic cholestasis, especially in alcoholic liver cirrhosis, and also indicates an inherited derangement of bilirubin transport mechanisms.
In chronic liver damage, particularly when alcohol-related, the transition of a secondary coproporphyrinuria to a chronic hepatic porphyria is not rare and is characterized by special urinary porphyrin constellations with high coproporphyrin components (Table 7). Besides, the absolute and especially the relative increase in heptacarboxyporphyrin within the entire porphyrin pathway shows a transition to chronic hepatic porphyria caused by an incipient lack of uroporphyrinogen decarboxylase. The following urinary and hepatic porphyrin ratios are biochemical indicators for the transition of secondary coproporphyrinuria to chronic hepatic porphyria: the urinary uroporphyrin/coproporphyrin ratio as well as the hepatic uroporphyrin/protoporphyrin ratio. Both ratios are <1 in secondary coproporphyria; a progression into chronic hepatic porphyria can be documented by the inversion of these ratios.
|
ALCOHOL AND PROTOPORPHYRINAEMIA
Protoporphyrinaemia is of various origins (Labbe and Nielsen, 1976). In alcoholics it can be explained by ferrochelatase inhibition if blood lead levels are normal, since lead intoxication is implicated in the development of protoporphyrinaemia. Protoporphyrin is present as a zinc chelate both in alcohol- and lead-induced protoporphyrinaemia. The alcohol-mediated inhibition of ferrochelatase will lead to alcohol-induced anaemia in chronic alcoholism. Alcohol reduces concentrations of pyridoxal 5-phosphate, which has been postulated as an essential cofactor for ferrochelatase (Labbe and Nielsen, 1976
). Probably, the depressed ferrochelatase and coproporphyrinogen oxidase activities in alcoholics are causally related to the increased bone marrow
-aminolevulinic acid synthase in patients with the acute reversible sideroblastic anaemia of alcoholics (Fraser and Schacter, 1980
) in contrast to idiopathic sideroblastic anaemia (Bottomley et al., 1973
).
INTERFERENCE BETWEEN ALCOHOL- AND LEAD-INDUCED ENZYME INHIBITION AND CORRESPONDING HEREDITARY ENZYME DEFICIENCIES IN THE HAEM PATHWAY
Acute lead poisoning represents an exogenous toxic porphyria on the basis of clinical and biochemical analogies to hereditary hepatic acute intermittent porphyria and coproporphyria. In both acute hepatic porphyrias and acute lead poisoning, abdominal pain, constipation, and peripheral neuropathy predominate (Doss, 1986, 1987
). Pathobiochemically, in acute lead poisoning an extremely high excretion of
-aminolevulinic acid and coproporphyrin (~90% isomer III) in urine, as well as an increase of protoporphyrin (mainly as zinc protoporphyrin) in the erythrocytes, was shown. This accumulation of porphyrins and their precursors is due to the inhibition of the haem-biosynthetic enzymes by lead, at the
-aminolevulinic acid dehydratase, coproporphyrinogen oxidase, and ferrochelatase steps.
Regarding the enzyme defects caused by lead, an interference with alcohol ingestion is possible; because the metabolic effects of lead and alcohol on haem-biosynthetic sequences catalysed by -aminolevulinic acid synthase,
-aminolevulinic acid dehydratase, coproporphyrinogen oxidase, and ferrochelatase are similar in principle (Table 8
). This means that alcohol can potentiate the rapid enzyme inhibition by lead, as well as prolong the hepatic and erythropoietic phase of lead intoxication (Doss, 1982
).
|
TREATMENT
Treatment of acute porphyrias includes the omission of precipitating factors, symptomatic measures according to the drug lists and regulatory treatment by glucose or haem (Mustajoki and Nordmann, 1993; Kaupinen et al., 1994
). Both glucose and haem have been shown to normalize the excessive production of haem precursors, as well as to lead to a clinical improvement (Doss, 1982
; Doss et al., 1985
; Kappas et al., 1995
; Schoenfeld et al., 1995
). Low-dose chloroquine therapy is a safe and highly effective treatment of extrahepatic manifestations of chronic hepatic porphyria, due to mobilization and elimination of high-carboxylated porphyrins from the liver cells and body tissue (Köstler and Doss, 1993
; Drago et al., 1995
; Freesemann et al., 1995
; Kappas et al., 1995
). Phlebotomy is also effective, but contraindicated in patients with liver cirrhosis, because of the high protein loss.
Apart from these therapeutic measures used during an acute phase of the porphyria disease process, prevention of recurrent attacks is of special interest for the treatment of acute and chronic hepatic porphyrias in the latent or subclinical phase. This includes the omission (avoidance) of alcohol, fasting (Goldberg et al., 1981; Doss et al., 1982
; Doss, 1985
; Thunell et al., 1992
), porphyrinogenic drugs (Wetterberg, 1976
; Kappas et al., 1995
; Doss et al., 1997
) and oestrogenic steroids. Also gene carriers should avoid alcohol consumption for prophylactic reasons. Besides, individual alcohol tolerance seems to be modulated in porphyria patients by nutritional conditions and other, not clearly elucidated, metabolic factors. Different types of alcoholic beverages seem to have different influences on the clinical outbreak of latent porphyria. Red wine and whisky seem to produce porphyria symptoms more often, whereas white wine and beer are better tolerated (Thunell et al., 1992
).
GENERAL CONCLUSIONS AND COMMENTS
Alcohol is an important precipitating and aggravating factor in human hereditary porphyrias: it is most important for PCT, including latent phases of chronic hepatic porphyria, but it is also important for the expression of the polysymptomatic acute hepatic porphyrias. In addition, alcohol ingestion will present a pathogenetic factor for the expression and/or aggravation of the potential hepatobiliary involvement in erythropoietic protoporphyria. In healthy subjects and patients with alcoholic liver syndromes, alcohol can produce a secondary coproporphyrinuria which is not of clinical relevance and does not lead to clinical symptoms because of this porphyrin abnormality. In patients with liver injury, however, alcohol could trigger the transition of a secondary coproporphyrinuria into a chronic hepatic porphyria.
The main reasons for these effects of alcohol are the inhibition of uroporphyrinogen decarboxylase and the induction of -aminolevulinic acid synthase in the liver. Alcohol interferes with a pre-existing uroporphyrinogen decarboxylase defect in chronic hepatic porphyria (membrane disease) and augments the inducibility of
-aminolevulinic acid synthase in the pharmacogenetic acute hepatic porphyria (regulatory disease). Along with this mechanism, synergistic forces between the primary enzyme deficiency, the depression of several haem biosynthetic enzymes by alcohol (inhibition of
-aminolevulinic acid dehydratase, coproporphyrinogen oxidase, and ferrochelatase and induction of uroporphyrinogen synthase), and an altered drug metabolism may be responsible for the potentiation of the porphyrinogenic effect of alcohol.
Abstinence from alcohol is a therapeutically and prophylactically important measure in all types of symptomatic hepatic porphyrias as well as in erythropoietic protoporphyria with hepatobiliary involvement. Also in gene carriers and patients in the subclinical latent phase of the disease process, alcohol consumption should be avoided, for prophylactic reasons.
From clinical experience, it follows that in cases with chronic consumption of alcohol, fatty liver, alcohol-induced hepatitis and liver cirrhosis, porphyrin studies in urine should be made to diagnose a hepatic porphyria in the latent phase. When dealing with abdominal and cutaneous symptoms in the clinical context with consumption of alcohol, one has to exclude a hepatic porphyria by differential diagnosis.
ACKNOWLEDGEMENTS
The study was in part supported by the German Research Association (grant Gr 1363) and the Hans-Fischer-Gesellschaft, Munich.
FOOTNOTES
* Author to whom correspondence should be addressed at: Abteilung für Klinische Biochemie, Klinikum der Philipps-Universität, Deutschhausstraße 17, D-35037 Marburg (Lahn), Germany.
REFERENCES
Abdulla, M., Haeger-Aronsen, B. and Sevensson, S. (1976) Effect of ethanol and zinc on ALA-dehydratase activity in red blood cells. Enzyme 21, 248252.[ISI][Medline]
Alkondon, M., Costa, A. C. S., Radhakrishnan, V., Aronstam, R. S. and Albuquerque, E. X. (1990) Selective blockade of NMDA activated channel currents may be implicated in learning deficits caused by lead. FEBS Letters 261, 124130.[ISI][Medline]
Altmann, L., Sveinsson, K. and Wiegand, H. (1991) Long-term potentiation in rat hippocampal slices is impaired following acute lead perfusion. Neuroscience Letters 128, 109112.[ISI][Medline]
Anderson, P. M. and Desnick, R. J. (1979) Purification and properties of -aminolevulinate dehydratase from human erythrocytes. Journal of Biological Chemistry 254, 69246930.[ISI][Medline]
Aubin, H. J., Laureaux, C., Tilikete, S., Gillet, C., Lepetitcorps, A., Nguyen, T., Troupel, S., Paille, F. and Barrucand, D. (1997) How useful is aminolevulinic acid dehydratase as a marker of recent alcohol intake? Addiction Biology 2, 225228.[ISI]
Barton, J. C. and Conrad, M. E. (1978) Effects of ethanol on the absorption and retention of lead. Proceedings of the Society for Experimental Biology and Medicine 159, 213218.
Beattie, D. S., Patton, G. M. and Rubin, E. (1973) The control of -aminolevulinic acid synthase in rat liver mitochondria. Effect of pyrazole on the apparent induction. Enzyme 16, 252257.[ISI][Medline]
Bel, A. and Girard, D. (1980) Porphyrie cutanea tardive avec antigene HBs et hepatite chronique aggressive. Nouvelle Presse Medicale 9, 2027.
Blauvelt, A. (1996) Hepatitis C virus and human immunodeficiency virus infection can alter porphyrin metabolism and lead to porphyria cutanea tarda. Archives of Dermatology 132, 15031504.[ISI][Medline]
Blauvelt, A., Harris, H. R., Hogan, D. J., Jimenez Acosta, F., Ponce, I. and Pardo, R. J. (1992) Porphyria cutanea tarda and human immunodeficiency virus infection. International Journal of Dermatology 31, 474479.[ISI][Medline]
Blitzer, R. D., Gil, O. and Landau, E. M. (1990) Long-term potentiation in rat hippocampus is inhibited by low concentrations of ethanol. Brain Research 537, 203208.[ISI][Medline]
Bloomer, J. R. (1976) The hepatic porphyrias. Pathogenesis, manifestations, and management. Gastroenterology 71, 689701.[ISI][Medline]
Bloomer, J. R. (1982) Protoporphyria. Seminars in Liver Disease 2, 143153.[Medline]
Bonkowsky, H. G. and Pomeroy, J. S. (1977) Human hepatic -aminolaevulinate synthase: requirement of an exogenous system for succinyl-co-enzyme A generation to demonstrate increased activity in cirrhotic and anticonvulsant-treated subjects. Clinical Science and Molecular Medicine 52, 509521.[ISI][Medline]
Bottomley, S. S., Tanaka, M. and Self, J. (1973) -aminolevulinic acid synthetase activity in normal human bone marrow and in patients with idiopathic sideroblastic anemia. Enzyme 16, 138145.[ISI][Medline]
Brodie, M. J., Thompson, G. C., Moore, M. R., McColl, K. E. L., Goldberg, A., Hardie, R. A. and Hunter, J. A. A. (1979) Haem biosynthesis in cutaneous hepatic porphyria: comparison with alcoholism and liver disease. Acta Hepatogastroenterologica 26, 122128.
Brugsch, J. T. (1937) Toxic porphyrinuria following chronic alcoholism. Proceedings of the Staff Meetings of the Mayo Clinic 12, 609613.
Calvert, G.M., Haring Sweeney, M., Fingerhut, M. A., Hornung, R. W. and Halperin, W. E. (1994) Evaluation of porphyria cutanea tarda in U.S. workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. American Journal of Industrial Medicine 25, 559571.[ISI][Medline]
Cederbaum, A. I. and Rubin, E. (1975) Molecular injury to mitochondria produced by ethanol and acetaldehyde. Federation Proceedings 34, 20452051.[ISI][Medline]
Cox, T. C., Bawden, M. J., Martin, A. and May, B. K. (1991) Human erythroid 5-aminolevulinate synthase: Promotor analysis and identification of an iron-responsive element in the mRNA. EMBO Journal 10, 18911902.[Abstract]
Cribier, B., Petiau, P., Keller, F., Schmitt, C., Vetter, D., Heid, E. and Grosshaus, E. (1995) Porphyria cutanea tarda and hepatitis C viral infection. A clinical and virologic study. Archives of Dermatology 131, 801804.[Abstract]
Cripps, D. J. (1987) Diet and alcohol effects on the manifestation of hepatic porphyrias. Federation Proceedings 46, 18941900.[ISI][Medline]
Dandekar, T., Stripecke, R., Gray, N. K., Goossen, B., Constable, A., Johansson, H. E. and Hentze, M. W. (1991) Identification of a novel iron responsive element in urine and human erythroid 5-aminolevulinate acid synthase mRNA. EMBO Journal 10, 19031909.[Abstract]
Delfau-Larue, M. H., Martasek, P. and Grandchamp, B. (1994) Coproporphyrinogen oxidase: gene organization and description of a mutation leading to exon 6 skipping. Human Molecular Genetics 3, 13251330.[Abstract]
De Matteis, F. (1998) Porphyria cutanea tarda of the toxic and sporadic varieties. Clinics in Dermatology 16, 265275.[ISI][Medline]
Deybach, J. Ch, Puy, H., Robréau, A. M., Lamoril, J., da Silva, V., Grandchamp, B. and Nordmann, Y. (1996) Mutations in the protoporphyrinogen oxidase gene in patients with variegate porphyria. Human Molecular Genetics 5, 407410.
Doss, M. (1980) Pathobiochemical transition of secondary coproporphyrinuria to chronic hepatic porphyria in humans. Klinische Wochenschrift 58, 141148.[ISI][Medline]
Doss, M. (1982) Hepatic porphyrias: Pathobiochemical, diagnostic, and therapeutic implications. In Progress in Liver Diseases, Popper, H. and Schaffner, F. eds, pp. 573597. Grune & Stratton, New York.
Doss, M. O. (1985) Alcohol and porphyrin metabolism. In Alcohol Related Disease in Gastroenterology, Seitz, H. K. and Kommerell, B. eds, pp. 232252. Springer, Berlin.
Doss, M. O. (1986) Lead intoxication as toxogenetic disease. Bollettino dell'Istituto Dermatologico S. Gallicano XIII, 115122.
Doss, M. O. (1987) Porphyrinurias and occupational disease. Annals of the New York Academy of Sciences 514, 204218.[Abstract]
Doss, M. O. (1990) Pathologie und Therapie der Porphyria cutanea tarda. Deutscher Dermatologe 38, 592597.
Doss, M. O. and Gross, U. (1997) Hepatic porphyrias. In New Trends in Hepatology 1996, Gerok, W., Loginov, A. S. and Pokrowskij, V. I. eds, pp. 195223. Kluwer, Dordrecht.
Doss, M. O. and Sassa, S. (1994) The porphyrias. In Laboratory Medicine. The Selection and Interpretation of Clinical Laboratory Studies, Noe, D. A. and Rock, R. C. eds, pp 535553. Williams & Wilkins, Baltimore.
Doss, M. O. and Sieg, I. (1995) Alkohol und Porphyrinstoffwechsel. In Handbuch Alkohol, Alkoholismus, alkoholbedingte Organschäden, Seitz, H. K., Lieber, C. S. and Simanowski, U. A. eds, pp. 167189. Johann Ambrosius Barth, Leipzig.
Doss, M. O., Nawrocki, P., Schmidt, A., Strohmeyer, G., Egbring, R., Schimpff, G., Dölle, W. and Korb, G. (1971) Einfluß von Diät, Glycin und Alkohol auf die Porphyrinurie bei chronischer hepatischer Porphyrie. Deutsche Medizinische Wochenschrift 96, 12291231.[ISI][Medline]
Doss, M., Look, D., Henning, H., Nawrocki, P., Schmidt, A., Dölle, W., Korb, G., Lüders, C. J. and Strohmeyer, G. (1972) Hepatic porphyrins and urinary porphyrins and porphyrin precursors in liver cirrhosis. Klinische Wochenschrift 50, 10251032.[ISI][Medline]
Doss, M., von Tiepermann, R., Stutz, G. and Teschke, R. (1980) Uroporphyrinogen decarboxylase inhibition in rat liver after alcohol ingestion. Medical Science 8, 562.
Doss, M., von Tiepermann, R., Stutz, G. and Teschke, R. (1981) Alcohol-induced decrease in uroporphyrinogen decarboxylase activity in rat liver and spleen. Enzyme 26, 2431.[ISI][Medline]
Doss, M. O., Baumann, H. and Sixel, F. (1982) Alcohol in acute porphyria. Lancet II, 1307.
Doss, M., Sauer, H., von Tiepermann, R. and Colombi, A. M. (1984) Development of chronic hepatic porphyria (porphyria cutanea tarda) with inherited uroporphyrinogen decarboxylase deficiency under exposure to dioxin. International Journal of Biochemistry 16, 369373.[ISI][Medline]
Doss, M., Sixel-Dietrich, F. and Verspohl, F. (1985) Glucose effect and rate limiting function of uroporphyrinogen synthase on porphyrin metabolism in hepatocyte culture: relationship with human acute hepatic porphyrias. Journal of Clinical Chemistry and Clinical Biochemistry 23, 505513.[ISI][Medline]
Doss, M. O., Benkmann, H. G. and Goedde, H. W. (1986) -aminolevulinic acid dehydratase (porphobilinogen synthase) in two families with inherited enzyme deficiency. Clinical Genetics 30, 191198.[ISI][Medline]
Doss, M. O., Frank, M. and Braun-Falco, O. (1991) Porphyria cutanea tarda: erythrocyte decarboxylase activity in 471 consecutive patients. Current Problems in Dermatology 20, 97105.[Medline]
Doss, M. O., Honcamp, M. and Frank M. (1997) Arzneistoffe bei akuten hepatischen Porphyrien und Empfehlungen zur Anästhesie. In Rote Liste 1997, Cantor, E. ed, pp. 47980. Aulendorf/Württ.
Doss, M. O., Gross, U., Lamoril, J., Kranl, C., Jacob, K., Doss, M., da Silva, V., Freesemann, A. G., Deybach, J-Ch., Sepp, N. and Nordmann, Y. (1999) Compound heterozygous hereditary coproporphyria with fluorescing teeth. Annals of Clinical Biochemistry 36, 680682.[ISI][Medline]
Drago, F., Battifoglio M. L., Gelati, G. and Rebora, A. (1995) Very low-dose chloroquine treatment for porphyria cutanea tarda. Acta Dermato-Venerelogica 75, 329330.
Eales, L. (1979) Porphyria and the dangerous life-threatening drugs. South African Medical Journal 56, 914917.[ISI][Medline]
Elder, G. H. (1976) Acquired disorders of haem synthesis. Essays in Medical Biochemistry 2, 75114.
Elder, G. H. (1998) Porphyria cutanea tarda. Seminars in Liver Disease 18, 6776.[ISI][Medline]
Elder, G. H. and Nordmann, Y. (1990) The molecular biology of porphyrias. In A Century of Porphyria, Vol. 11, Moore, M. R. ed., pp. 125133. Pergamon Press, London.
Elder, G. H., Evans, J. O. and Matlin, S. A. (1976) The effect of the porphyrinogenic compound, hexachlorobenzene, on the activity of hepatic uroporphyrinogen decarboxylase in the rat. Clinical Science and Molecular Medicine 51, 7180.[ISI][Medline]
Fargion, S., Piperno, A., Cappellini, M. D., Sampietro, M. and Fracanzani, A.L. (1992) Hepatitis C virus and porphyria cutanea tarda: Evidence of a strong association. Hepatology 16, 13221326.[ISI][Medline]
Ferri, C., Baicchi, U., La Civita, L., Greco, F., Longombardo, G. and Mazzoni, A. (1993) Hepatitis C virus-related autoimmunity in patients with porphyria cutanea tarda. European Journal of Clinical Investigation 23, 851855.[ISI][Medline]
Franke, K. and Fikentscher, R. (1935) Die Bedeutung der quantitativen Porphyrinbestimmung mit der Lumineszenzmessung für die Prüfung der Leberfunktion und für Ernährungsfragen. Münchener Medizinische Wochenschrift 82, 171172.
Fraser, M. B. and Schacter, B. A. (1980) Increased bone marrow delta-aminolevulinic acid synthetase activity in the acute reversible sideroblastic anemia of alcoholics. American Journal of Hematology 8, 149156.[ISI]
Freesemann, A., Frank, M., Sieg, I. and Doss, M. O. (1995) Treatment of porphyria cutanea tarda by the effect of chloroquine on the liver. Skin Pharmacology 8, 156161.[ISI][Medline]
Freesemann, A. G., Gross, U., Bensidhoum, M., de Verneuil, H. and Doss, M. O. (1998) Immunological, enzymatic and biochemical studies of uroporphyrinogen III-synthase deficiency in 20 patients with congenital erythropoietic porphyria. European Journal of Biochemistry 257, 149153.[Abstract]
Fujita, H., Koizumi, A., Furusawa, T. and Ikeda, M. (1987) Decreased erythrocyte -aminolevulinate dehydratase activity after styrene exposure. Biochemical Pharmacology 36, 711716.[ISI][Medline]
Fujita, H., Kondo, M., Taketani, S., Nomura, N., Furuyama, K., Akagi, R., Nagai, T., Terajima, M., Galbraith, R. A. and Sassa, S. (1994) Characterization and expression of cDNA encoding coproporphyrinogen oxidase from a patient with hereditary coproporphyria. Human Molecular Genetics 3, 18071810.[Abstract]
Garey, J. R., Franklin, K. F., Brown, D. A., Harrison, L. M., Metcalf, K. M. and Kushner, J. P. (1993) Analysis of uroporphyrinogen decarboxylase complementary DNAs in sporadic porphyria cutanea tarda. Gastroenterology 105, 165169.[ISI][Medline]
Garey, R., Harrison, L. M., Franklin, K. F., Metcalf, K. M., Radisky, E. S. and Kushner, J. P. (1990) Uroporphyrinogen decarboxylase: a splice site mutation causes the deletion of exon 6 in multiple families with porphyria cutanea tarda. Journal of Clinical Investigation 86, 14161422.[ISI][Medline]
Goldberg, A. and Rimington, C. (1962) Diseases of porphyrin metabolism, pp. 1920. Thomas, Springfield.
Goldberg, A., McColl, K. E. L. and Moore, M. R. (1981) Alcohol and porphyria. Lancet II, 905906.
Gouya, L., Deybach, J. Ch., Lamoril, J., da Silva, V., Beaumont, C., Grandchamp, B. and Nordmann, Y. (1996) Modulation of the phenotype in dominant erythropoietic protoporphyria by a low expression of the normal ferrochelatase allele. American Journal of Human Genetics 58, 292299.[ISI][Medline]
Gouya, L., Puy, H., Lamoril, J., Da Silva, V., Grandchamp, B., Nordmann, Y. and Deybach, J.-C. (1999) Inheritance in erythropoietic protoporphyria: a common wild-type ferrochelatase allelic variant with low expression accounts for clinical manifestation. Blood 93, 21052110.
Grandchamp, B., Lamoril, J. and Puy, H. (1995) Molecular abnormalities of coproporphyrinogen oxidase in patients with hereditary coproporphyria. Journal of Bioenergetics and Biomembranes 27, 215219.[ISI][Medline]
Grossmann, M. E., Bickers, D. R., Poh-Fitzpatrick, M. B., Deleo, V. A. and Harber, L. C. (1979) Porphyria cutanea tarda. Clinical features and laboratory findings in 40 patients. American Journal of Medicine 67, 277286.[ISI][Medline]
Groß, U., Honcamp, M., Daume, E., Frank, M., Düsterberg, B. and Doss, M. O. (1995) Hormonal oral contraceptives, urinary porphyrin excretion and porphyrias. Hormone and Metabolic Research 27, 379383.[ISI][Medline]
Groß, U., Honcamp, M. and Doss, M. O. (1996) Heterogeneity of AIP: a subtype with normal PBG deaminase activity in erythrocytes in Germany. European Journal of Clinical Chemistry and Clinical Biochemistry 34, 613618.[ISI][Medline]
Groß, U., Sassa, S., Jacob, K., Deybach, J-C., Nordmann, Y., Frank, M. and Doss, M. O. (1998) 5-aminolevulinic acid dehydratase deficiency porphyria: a twenty-year clinical and biochemical follow-up. Clinical Chemistry 44, 18921896.
Grover, C. A., Frye, G. D. and Griffith, W. H. (1994) Acute tolerance to ethanol inhibition of NMDA-mediated EPSPs in CA1 region of the rat hippocampus. Brain Research 642, 7076.[ISI][Medline]
Grover, C. A., Jasek, M. C., Frye, G. D. and Griffith, W. H. (1997) Ethanol inhibition of reduced frequency-dependent rundown of calcium currents in acutely dissociated MS/nDB neurons from chronic in vivo lead-exposed adult rats. Neurotoxicology 18, 179190.[ISI][Medline]
Habermann, H. F., Rosenberg, F. and Menon, I. A. (1975) Porphyria cutanea tarda: comparison of cases precipitated by alcohol and estrogens. Canadian Medical Association Journal 113, 653655.[Abstract]
Hahn, M. and Bonkovsky, H. L. (1997) Multiple chemical sensitivity syndrome and porphyria. Archives of Internal Medicine 157, 281285.[Abstract]
Hamlyn, A. N., Hopper, J. C. and Skillen, A. W. (1979) Assessment of erythrocyte -aminolevulinate dehydratase for outpatient detection of alcoholic liver disease: comparison with
-glutamyltransferase and casual blood ethanol. Clinica Chimica Acta 95, 453459.[ISI][Medline]
Harigae, H., Suwabe, N., Weinstock, P. H., Nagai, M., Fujita, H., Yamamoto, M. and Sassa, S. (1998) Deficient heme and globin synthesis in embryonic stem cells lacking the erythroid-specific -aminolevulinate synthase gene. Blood 91, 798805.
Held, H. (1977) Effect of alcohol on the heme and porphyrin synthesis interaction with phenobarbital and pyrazole. Digestion 15, 136146.[ISI][Medline]
Held, J. L., Sassa, S., Kappas, A. and Harber, L. C. (1989) Erythrocyte uroporphyrinogen decarboxylase activity in porphyria cutanea tarda: a study of 40 consecutive patients. Journal of Investigative Dermatology 93, 332334.[Abstract]
Henriksson, M., Timonen, K., Mustajoki, P., Pihlaja, H., Tenhunen, R., Peltonen, L. and Kauppinen, R. (1996) Four novel mutations in the ferrochelatase gene among erythropoietic protoporphyria patients. Journal of Investigative Dermatology 106, 346350.[Abstract]
Hift, R. and Kirsch, R. E. (1995) Porphyria cutanea tarda. In Alcoholic Liver Disease, Hall, P. ed., pp. 219228. Edward Arnold, London.
Hindmarsh, J. T. (1998) Enzyme assays and the porphyrias: which tissues and when indicated. Clinical Dermatology 16, 245250.[ISI][Medline]
Ishida, N., Fujita, H., Fukuda, Y., Noguchi, T., Doss, M., Kappas, A. and Sassa, S. (1992) Cloning and expression of the defective genes from a patient with -aminolevulinate dehydratase porphyria. Journal of Clinical Investigation 89, 14311437.[ISI][Medline]
Jones, R. E. and Chelsky, M. (1986) Further discussion concerning porphyria cutanea tarda and TCDD exposure. Archives of Environmental Health 41, 100103.[ISI][Medline]
Kalow, W. (1962) Pharmacogenetics. Heredity and the Response to Drugs. Saunders, Philadelphia.
Kaplowitz, N., Javitt, N. and Kappas, A. (1972) Coproporphyrin I and III excretion in bile and urine. Journal of Clinical Investigation 51, 28952899.[ISI][Medline]
Kappas, A., Sassa, S., Galbraith, A. and Nordmann, Y. (1995) The porphyrias. In The Metabolic and Molecular Bases of Inherited Disease, Scriver, C. R., Beaudet, A. L., Sly, W. S. and Vale, D. eds, pp. 21032159. McGraw-Hill, New York.
Kaupinen, R., Timonen, K. and Mustajoki, P. (1994) Treatment of the porphyrias. Annals of Medicine 26, 3138.[ISI][Medline]
Keithly, J. H. and Nudler, K. D. (1983) Protoporphyrin formation in Rhizobium japonicum. Journal of Bacteriology 154, 838845.[ISI][Medline]
Kodama, T., Kondo, M., Urata, G., Satoh, H., Ohtake, H., Iwasaki, Y., Itakura, H., Ohkubo, A. and Kosaka, K. (1983) Changes in aminolevulinate synthase and aminolevulinate dehydratase activity in cirrhotic liver. Gastroenterology 84, 236241.[ISI][Medline]
Kondo, M., Urata, G. and Shimizu, Y. (1983) Decreased liver -aminolaevulinate dehydratase activity in porphyria cutanea tarda and in alcoholism. Clinical Science 65, 423428.[ISI][Medline]
Köstler, E. and Doss, M. O. (1993) Porphyria cutanea tarda (chronische hepatische Porphyrie). In Ergebnisse der inneren Medizin und Kinderheilkunde, Vol. 61, pp. 124170. Springer-Verlag, Berlin.
Koszo, F., Horvath, L. I., Simon, N., Siklosi, C. S. and Kiss, M. (1982) The role of possible membrane damage in porphyria cutanea tarda: a spin label study of rat liver cell membranes. Biochemical Pharmacology 31, 1117.[ISI][Medline]
Krasner, N., Moore, M. R., Thompson, G. G., McIntosh, W. and Goldberg, A. (1974) Depression of erythrocyte -aminolaevulinate acid dehydratase activity in alcoholics. Clinical Science and Molecular Medicine 46, 415418.[ISI][Medline]
Labbe, R. F. and Nielsen, L. (1976) Clinicalbiochemical interpretations of erythrocyte protoporphyrin. Ferrochelatasepyridoxal phosphate studies. In Porphyrins in Human Diseases, Doss, M. ed., pp. 141147. Karger, Basel.
Labbe, R. F., Nutter, J., Cowger, M. L. and Nielsen, L. D. (1970) Control of heme biosynthesis. Effect of nicotinamide adenine dinucleotide on the induction of delta-aminolaevulinic acid synthase. Biochemical Medicine 3, 465474.[ISI][Medline]
Lacour, J. P., Bodokh, I., Castanet, J., Bekri, S. and Ortonne, J. P. (1993) Porphyria cutanea tarda and antibodies to hepatitis C virus. British Journal of Dermatology 128, 121123.[ISI][Medline]
Lamoril, J., Martasek, P., Deybach, J.-C., da Silva, V., Grandchamp, B. and Nordmann, Y. A. (1995) Molecular defect in coproporphyrinogen oxidase gene causing harderoporphyria, a variant form of hereditary coproporphyria. Human Molecular Genetics 4, 275278.[Abstract]
Lamoril, J., Deybach, J. C., Puy, H., Grandchamp, B. and Nordmann, Y. (1997) Three novel mutations in the coproporphyrinogen oxidase gene. Human Mutation 9, 7880.[ISI][Medline]
Lane, S. E. and Stewart, M. E. (1983) Alcohol-mediated effects on the level of cytochrome P-450 and heme biosynthesis in cultured rat hepatocytes. Biochimica et Biophysica Acta 755, 313317.[ISI][Medline]
Lefkowitch, J. H. and Grossmann, M. E. (1983) Hepatic pathology in porphyria cutanea tarda. Liver 3, 1929.[ISI][Medline]
Li, F., Lim, C. K., Simpson, K. J. and Peters, T. J. (1989) Coproporphyrinogen oxidase, protoporphyrinogen oxidase and ferrochelatase activities in human liver biopsies with special reference to alcoholic liver disease. Journal of Hepatology 8, 8693.[ISI][Medline]
Li, F., Lim, C. K. and Peters, T. J. (1990) Coproporphyrinogen oxidase, protoporphyrinogen oxidase and ferrochelatase activities in iron-overloaded and ethanol-treated rats. Biomedical Chromatography 4, 253256.[ISI][Medline]
Lieber, C. S. (1980) Metabolism and metabolic effects of alcohol. Seminars in Hematology 17, 8599.[ISI][Medline]
Lindberg, R. L. P., Porcher, C., Grandchamp, B., Ledermann, B., Bürki, K., Brandner, S., Aguzzi, A. and Meyer, U. A. (1996) Porphobilinogen deaminase deficiency in mice causes neuropathy resembling that of human hepatic porphyria. Nature Genetics 12, 195199.[ISI][Medline]
Lobato, M. N. and Berger, T. G. (1988) Porphyria cutanea tarda associated with the acquired immunodeficiency syndrome. Archives of Dermatology 124, 10091010.[ISI][Medline]
Martasek, P., Nordmann, Y. and Grandchamp, B. (1994) Homozygous hereditary coproporphyria caused by an arginine to tryptophane substitution in coproporphyrinogen oxidase and common intragenic polymorphisms. Human Molecular Genetics 3, 477480.[Abstract]
Martinez, M.-V. R., Espinosa Aguilar, M. D., Sanchez-Vizcaino, J., Quintero Fuentes, D., Nogueras Lopez, F. and Lopez de Hierro Rinz, M. (1996) Association entre porfiria cutanea tarda y virus de la hepatitis C. Revista Espanola de Enfermedades Digestivas 88, 231236.[ISI][Medline]
Mazurier, F., Moreau-Gaudry, F., Salesse, S., Barbot, C., Ged, C., Reiffers, J. and de Verneuil, H. (1997) Gene transfer of the uroporphyrinogen III synthase cDNA into haematopoietic progenitor cells in view of a future gene therapy in congenital erythropoietic porphyria. Journal of Inherited Metabolic Disease 20, 247257.[ISI][Medline]
McColl, K. E. L., Thompson, G. G., Moore, M. R. and Goldberg, A. (1980) Acute ethanol ingestion and haem biosynthesis in healthy subjects. European Journal of Clinical Investigation 10, 107112.[ISI][Medline]
McColl, K. E. L., Moore, M. R., Thompson, G. G. and Goldberg, A. (1981) Abnormal haem biosynthesis in chronic alcoholics. European Journal of Clinical Investigation 11, 461468.[ISI][Medline]
McEwin, R. (1976) Porphyria in Australia. In Porphyrins in Human Diseases, Doss, M. ed., pp. 233244. Karger, Basel.
Mezey, E. (1976) Ethanol metabolism and ethanoldrug interactions. Biochemical Pharmacology 25, 869875.[ISI][Medline]
Moore, M. R. (1974) The effects of ethanol on haem biosynthesis. In Proceedings of the First International Symposium on Alcohol and Aldehyde Metabolizing Systems, Thurman, R. G. ed., p. 543. Academic Press, London.
Moore, M. R. (1980) International review of drugs in acute porphyria 1980. International Journal of Biochemistry 12, 10891097.[ISI][Medline]
Moore, M. R. (1998) The biochemistry of heme synthesis in porphyria and in the porphyrinurias. Clinics in Dermatology 16, 203223.[ISI][Medline]
Moore, M. R., Beattie, A. D., Thompson, G. G. and Goldberg, A. (1971) Depression of -aminolaevulinic acid dehydratase activity by ethanol in man and rat. Clinical Science 40, 8188.[ISI][Medline]
Moore, M. R., McColl, K. E. and Goldberg, A. (1984) The effects of alcohol on porphyrin biosynthesis and metabolism. Contemporary Issues in Clinical Biochemistry 1, 161187.[Medline]
Moran-Jimenez, M. J., Ged, C., Romana, M., de Salamanca, E., Taïeb, A., Topi, G., D'Alessandro, L. and de Verneuil, H. (1996) Uroporphyrinogen Decarboxylase: complete human gene sequence and molecular study of three families with hepatoerythropoietic porphyria. American Journal of Human Genetics 58, 712721.[ISI][Medline]
Mukerji, S. K., Pimstone, N. R. and Burns, M. (1984) Dual mechanism of inhibition of rat liver uroporphyrinogen decarboxylase activity by ferrous iron: its potential role in the genesis of porphyria cutanea tarda. Gastroenterology 87, 12481254.[ISI][Medline]
Mukerji, S. K., Saicheur, T. and Pimstone, N. R. (1997) Alcohol metabolism in liver disease may trigger clinical porphyria cutanea tarda because iron released from ferritin inhibits uroporphyrinogen decarboxylase activity and induces hepatic lipid peroxidation. Acta Haematologica 98, 452.
Mustajoki, P. and Nordmann, Y. (1993) Early administration of heme arginate for acute porphyric attacks. Archives of Internal Medicine 153, 20042008.[Abstract]
Mustajoki, P., Kauppinen, R., Lannfelt, L. and Koistinen, J. (1992) Frequency of low PBG deaminase activity in Finland. Journal of Internal Medicine 231, 389395.[ISI][Medline]
Navas, S., Bosch, O., Castillo, I., Marriott, E. and Carreno, V. (1995) Porphyria cutanea tarda and hepatitis C and B viruses infection: a retrospective study. Hepatology 21, 279284.[ISI][Medline]
Nordmann, Y. (1991) Human hereditary porphyrias. In Oxford Textbook of Clinical Hepatology, McIntyre, N., Benhamou, J.-P., Bircher, J., Rizzetto, M. and Rodes, J. eds, pp. 974985. Oxford University Press, Oxford.
Nordmann, Y., de Verneuil, H., Deybach, J.-C., Delfau, M. H. and Grandchamp, B. (1990) Molecular genetics of porphyrias. Annals of Medicine 22, 387391.[ISI][Medline]
Orten, J. M., Doehr, S. A., Bond, C., Johnson, H. and Pappas, A. (1963) Urinary excretion of porphyrins and porphyrin intermediates in human alcoholics. Quarterly Journal of Studies on Alcohol 24, 598609.[ISI]
Ostrowski, J., Kosecki, P., Martynska, M. and Milewski, B. (1984) Urinary porphyrins in liver disease. Scandinavian Journal of Gastroenterology 19, 862866.[ISI][Medline]
Pennington, S. N., Smith, C. P. and Tapseott, E. B. (1978) Effect of an acute dose of ethanol on rat liver microsomal mixed function oxygenase components and membrane lipid composition. Alcoholism: Clinical and Experimental Research 2, 311316.[ISI][Medline]
Polo, C. F., Afonso, S. G., Navone, N. M., Rossetti, M. V. and Del C Batlle, A. M. (1995) Zinc aminolevulinic acid dehydratase reactivation index as a tool for diagnosis of lead exposure. Ecotoxicology and Environmental Safety 32, 267272.[ISI][Medline]
Puy, H., Robréau, A. M., Rosipal, R., Nordmann, Y. and Deybach, J. Ch. (1996) Protoporphyrinogen oxidase: complete genomic sequence and polymorphisms in the human gene. Biochemical and Biophysical Research Communications 226, 226230.[ISI][Medline]
Puy, H., Deybach, J. C., Lamoril, J., Robreau, A. M., da Silva, V., Gouya, L., Grandchamp, B. and Nordmann, Y. (1997) Molecular epidemiology and diagnosis of PBG deaminase gene defects in acute intermittent porphyria. American Journal of Human Genetics 60, 13731383.[ISI][Medline]
Quecedo, L., Costa, J. and Enriquez de Salamanca, R. (1996) Papel del virus de la hepatitis C en la hepatopatia de la porfiria cutanea tarda. Medicina Clinica 106, 321324.[ISI][Medline]
Rubin, E. and Lieber, C. S. (1972) Alcoholism, alcohol, and drugs. Science 172, 10971102.[ISI]
Salmon, P. (1996) Hepatitis C virus infection and porphyria cutanea tarda in Australasia. Archives of Dermatology 132, 191.
Sarkany, R. P. E. and Cox, T. M. (1995) Autosomal recessive erythropoietic protoporphyria: a syndrome of severe photosensitivity and liver failure. Quarterly Journal of Medicine 88, 541549.[Abstract]
Sarkany, R. P. E., Alexander, G. J. M. A. and Cox, T. M. (1994) Recessive inheritance of erythropoietic protoporphyria with liver failure. Lancet 343, 13941396.[ISI][Medline]
Schoenfeld, N., Mamet, R., Dotan, I., Sztern, M., Levo, Y. and Aderka, D. (1995) Relation between uroporphyrin excretion, acute attacks of hereditary coproporphyria and successful treatment with haem arginate. Clinical Science 88, 365369.[ISI][Medline]
Schoenfeld, N., Mamet, R., Leibovici, L. and Lanir, A. (1996) Alcohol-induced changes in urinary aminolevulinic acid and porphyrins: Unrelated to liver disease. Alcohol 13, 5963.[ISI][Medline]
Schreiber, W. E., Zhang, X., Senz, J. and Jamani, A. (1997) Hereditary coproporphyria: Exon screening by heteroduplex analysis detects three novel mutations in the coproporphyrinogen oxidase gene. Human Mutation 10, 196200.[ISI][Medline]
Shanley, B. C., Zail, S. S. and Joubert, S. M. (1968) Effect of ethanol on liver aminolevulinate synthetase in rats. Lancet II, 7071.
Shanley, B. C., Zail, S. S. and Joubert, S. M. (1969) Effect of ethanol on liver -aminolevulinate synthase activity and urinary porphyrin excretion in symptomatic porphyria. British Journal of Haematology 17, 389396.[ISI][Medline]
Shemin, D. (1976) 5-Aminolaevulinic acid dehydratase: structure, function, and mechanism. Philosophical Transactions of the Royal Society of London Series BBiological Science 273, 109115.
Sieg, I., Doss, M. O., Kandels, H. and Schneider, J. (1991) Effect of alcohol on -aminolevulinic acid dehydratase and porphyrin metabolism in man. Clinica Chimica Acta 202, 211218.[ISI][Medline]
Soriano, E., Catala, M. T., Lacruz, J., Campayo, A., Lopez Aldeguer, J. and Perello, A. (1993) Porphyria cutanea tarda y infeccion por el virus de la immunodeficiencia humana. Revista Clinica Espanola 192, 120122.[ISI][Medline]
Stölzel, U., Köstler, E., Koszka, C., Stöffler-Meilicke, M., Schuppan, D., Somasundaram, R., Doss, M. O., Habermehl, K. O. and Riecken, E. O. (1995) Low prevalence of hepatitis C virus infection in porphyria cutanea tarda in Germany. Hepatology 21, 15001503.[ISI][Medline]
Strik, J. J. T. W. A. and Doss, M. (1978) Chronisch hepatische Porphyrie durch polyhalogenisierte aromatische Verbindungen bei Menschen. Therapiewoche 28, 84608466.
Susa, S., Daimon, M., Yamamori, I., Kondo, M., Yamatani, K., Sasaki, H. and Kato, T. (1998) A novel mutation of coproporphyrinogen oxidase (CPO) gene in a Japanese family. Journal of Human Genetics 43, 182184.[ISI][Medline]
Sutherland, D. A. and Watson, C. J. (1951) Studies on coproporphyrin. VI. The effect of alcohol on the per diem excretion and isomer distribution of the urinary coproporphyrins. Journal of Laboratory and Clinical Medicine 37, 2939.[ISI]
Teschke, R., Bolsen, K., Landmann, H. and Goertz, G. (1983) Effect of hexachlorobenzene on the activities of hepatic alcohol metabolizing enzymes. Biochemical Pharmacology 32, 17451751.[ISI][Medline]
Teschke, R., Gorys-Könemann, C., Daldrup, T. and Goerz, G. (1987) Influence of chronic alcohol consumption on hepatic heme and porphyrin metabolism. Biochemical Pharmacology 36, 11331138.[ISI][Medline]
Thunell, S., Floderus, Y., Henrichson, A., Moore, M. R., Meissner, P. and Sinclair, J. (1992) Alcoholic beverages in acute porphyria. Journal of Studies on Alcohol 3, 272276.
Topi, G. C., Amantea, A. and Griso, D. (1984) Recovery from porphyria cutanea tarda with no specific therapy other than avoidance of hepatic toxins. British Journal of Dermatology 111, 7582.[Medline]
Von Tiepermann, R., Koss, G. and Doss, M. (1980) Uroporphyrinogen decarboxylase deficiency in experimental chronic hepatic porphyria. Hoppe-Seyler's Zeitschrift für Physiologische Chemie 361, 12171222.[ISI][Medline]
Warnich, L., Kotze, M. J., Groenewald, I. M., Groenewald, J. Z., van Brakel, M. G., van Heerden, C. J., de Villiers, J. N. P., van de Ven, W. J. M., Schoenemakers, E. F. P. M., Taketani, S. and Retief, A. E. (1996) Identification of three mutations and associated haplotypes in the protoporphyrinogen oxidase gene in South African families with variegate porphyria. Human Molecular Genetics 5, 981984.
Wetterberg, L. (1976) Report on an international survey of safe and unsafe drugs in acute intermittent porphyria. In Porphyrins in Human Diseases Report of the Discussions, Doss, M. and Nawrocki, P. eds, pp. 191202. Falk Foundation, Freiburg.
Wissel, P. S., Sordillo, P., Anderson, K. E., Sassa, S., Savillo, R. L. and Kappas, A. (1987) Porphyria cutanea tarda associated with the acquired immune deficiency syndrome. American Journal of Dermatology 25, 107113.
Wright, D. J., Lim, C. K. and Peters, T. J. (1990) High performance liquid chromatographic studies of erythrocyte haem biosynthetic enzyme activities in alcoholic macrocytosis. Biomedical Chromatography 4, 249252.[ISI][Medline]