THE ROLE OF POLYMORPHISMS OF GLUTATHIONE S-TRANSFERASES GSTM1, M3, P1, T1 AND A1 IN SUSCEPTIBILITY TO ALCOHOLIC LIVER DISEASE

A. M. BRIND1,*, A. HURLSTONE2, D. EDRISINGHE3, I. GILMORE4, N. FISHER5, M. PIRMOHAMED3 and A. A. FRYER2

1 Department of Gastroenterology, 2 Human Genomics Research Group, Institute for Science and Technology in Medicine, Keele University School of Medicine, University Hospital of North Staffordshire, Stoke-on-Trent, Staffordshire, 3 Department of Pharmacology and Therapeutics, The University of Liverpool, Ashton Street, 4 Gastroenterology Unit, The Royal Liverpool and Broadgreen University Hospital Trust, Prescot Street, Liverpool and 5 Department of Gastroenterology, Dudley Group of Hospitals, Dudley, UK

* Author to whom correspondence should be addressed at: Department of Gastroenterology, University Hospital of North Staffordshire, Stoke-on-Trent, Staffordshire UK ST4 6QG. E-mail: alison.brind{at}uhns.nhs.uk

(Received 13 July 2004; first review notified 28 August 2004; in revised form 29 September 2004; accepted 1 October 2004)


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Aims and Methods: Oxidant stress is proposed to be an important pathogenic factor in liver damage related to alcohol. The glutathione S-transferases (GSTs) are a group of polymorphic enzymes that are important in protection against oxidant stress. As there is evidence for genetic susceptibility to alcohol-related liver disease we have compared the frequency of polymorphisms of GSTM1, M3, P1, T1 and A1 by polymerase chain reaction (PCR) on leucocyte DNA in patients from North Staffordshire, Birmingham and Liverpool with alcohol-related chronic liver disease heavy drinking and normal local controls. Results: There were no significant differences in GSTM1, GSTM3 or GSTP1 genotype frequencies among patients, drinking and non-drinking controls from the three centres. There was a significant increase in the GSTT1 null Liverpool alcoholic liver disease (ALD) patients compared with corresponding non-drinking controls (26.3 and 14.6%, respectively; P = 0.044, odds ratio (OR) = 2.1, 95% CI = 1.1–4.7) though this was not repeated in the Birmingham and North Staffordshire cohorts. For GSTA1, the –69 CC genotype was associated with increased risk of ALD in the Liverpool group, but a reduced risk in the North Staffordshire group. Conclusions: We have failed to demonstrate within the limitation of a case–control study a reproducible significant association of GST polymorphisms with susceptibility to ALD but there are suggestions that GSTA1 and GSTT1 warrant further study.


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Although liver damage is related to the amount of alcohol consumed, only 20% of those consuming >80 g per day develop chronic alcoholic liver disease (ALD) (Bellantani et al., 1994Go; Becker et al., 1996Go). Predisposition to ALD may be genetically determined as concordance rates for alcoholic cirrhosis are 14.6 and 5.4 in monozygotic and dizygotic twins, respectively (Hrubrec and Omenn, 1981Go). Indeed, 50% of the overall variance in susceptibility is due to genetic factors, influencing predisposition both to alcoholism and to subsequent alcohol-related tissue damage (Hrubrec and Omenn, 1981Go). There have been many case–control studies of polymorphisms in candidate genes and susceptibility to ALD including genes involved in alcohol metabolism, inflammation, immune response and tissue damage. However, few of these studies have provided conclusive reproducible results.

There is considerable evidence implicating reactive oxygen species (ROSs) and their products in the pathology of ALD (Arteel, 2003Go). ROSs are generated during alcohol metabolism as a result of the generation of both NADH from the conversion of ethanol to acetaldehyde by alcohol dehydrogenase and NADPH from the metabolism by cytochrome P450 2E1 (CYP2E1). In addition ROSs are generated by alcohol-related cell damage (Hoek and Pastoria, 2002Go), which suggests that ROSs are central to alcohol-related liver damage. ROSs are highly reactive and damage cellular macromolecules such as lipids, DNA and proteins (Arteel, 2003Go). Increased lipid peroxidation is seen in humans following alcohol consumption (Meagher et al., 1999Go) in rats, liver injury due to alcohol has been related to lipid peroxidation (Polavarapu et al., 1998Go). ROS lead to the activation of stellate cells (Tsukamoto et al., 1995Go) and up-regulation of NF{kappa}B (Roman et al., 1999Go).

Mammalian cells express a number of enzyme systems to detoxify ROSs and their by-products, including superoxide dismutase, glutathione peroxidase, glutathione S-transferases (GSTs) and catalase. It has been suggested that the inheritance of MnSOD-Val (Degoul et al., 2001Go) is associated with severe alcohol-related liver disease but this has not been confirmed in subsequent studies (Brind et al., 2003Go; Stewart et al., 2002Go).

The GST enzymes are believed to exert a critical role in cellular protection against ROSs. An increasing number of genes that encode these enzymes have been found to be polymorphic. Some of the allelic variants show impaired catalytic activity and have been found to be associated with diseases such as bronchial hyper-responsiveness (Hayes and Strange, 2000Go). GST expression is altered in the liver of patients with ALD (Harrison et al., 1990Go), and increased expression of microsomal and GST-{alpha} is associated with protection from pro-oxidant stress (Mari and Cederbaum, 2001Go). Early small case–control studies suggested an increased risk of alcoholism in patients with the GSTM1 null polymorphism (Harada et al., 1987Go). However, further studies have failed to demonstrate a significant association between liver disease and the GSTM1 null polymorphism, though two of these studies comprised very small numbers of patients (45 and 57 patients) (Groppi et al., 1997; Frenzer et al., 2002Go) and one had a modest number (120 patients) (Rodrigo et al., 1999Go). A further study found a non-significant reduction in GSTM1 null in heavy drinkers without liver disease (Savolainen et al., 1996Go). Interestingly, the GSTM1 null genotype has been associated with other forms of liver disease including primary biliary cirrhosis (Davies et al., 1993Go) and autoimmune hepatitis (Fukagawa et al., 2001Go). In contrast to GSTM1, there have been fewer studies of the other GST enzymes. No increase in GSTT1 null was found in 57 patients with alcoholic liver (Frenzer et al., 2002Go). Homozygosity for the GSTP1 Ile105 allele is increased in patients with cystic fibrosis who had significant liver disease (Henrion-Caude et al., 2002Go).

In view of these contradictory and incomplete results, we have performed an evaluation of well-characterized polymorphisms in multiple GST genes (GSTM1, M3, P1, T1, A1) in a large number of patients with ALD, heavy-drinking controls and healthy controls to evaluate whether polymorphisms in these enzymes increase the risk of ALD. GSTM1, P1 and T1 were selected in view of previous data. GSTM3 was also selected in the light of linkage disequilibrium between GSTM1 and M3 genotypes, whereas GSTA1 was included due to the high expression of GSTA1-1 in the liver and its activity towards the products of oxidative stress.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Patient recruitment
The ALD cases comprised subjects recruited from three centers: the Gastroenterology Department of the University Hospital of North Staffordshire, the Liver Unit at the Queen Elizabeth Hospital, Birmingham and the Gastroenterology Department of the Royal Liverpool Hospital. The recruitment criteria for the ALD cases are shown in Table 1.


View this table:
[in this window]
[in a new window]
 
Table 1. Characteristics of Alcohol Liver Disease patients from each centre

 
North Staffordshire. Alcohol consumption in ALD patients and drinking controls was defined as >50 units per week in females and >60 units in males, as determined by a structured questionnaire. Chronic liver disease was defined as twice the upper limit of the normal range for alkaline phosphatase (ALP), alanine transaminase (ALT) or bilirubin on at least two occasions within three months. The patients in the drinking control group had normal liver function tests (LFTs) (except for isolated increases in gamma-glutamyl transferase) and no clinical evidence of liver disease. Normal population controls comprised hospital-based controls who had no evidence of inflammatory or malignant pathology.

Birmingham. ALD cases comprised patients with a history of alcohol abuse and decompensated liver disease [i.e. presenting with jaundice (bilirubin > 100 mM), variceal haemorrhage or ascites] who were seen at the Birmingham Liver Unit. The confirmation of ALD by a liver biopsy was available in 76% of cases. Healthy controls included spouses of the affected patients and members of the hospital workforce.

Liverpool. ALD was diagnosed on the basis of either a positive biopsy (30%) and/or unequivocal clinical signs and symptoms of portal hypertension when biopsy was contraindicated or felt to be clinically unnecessary. All patients had a clinical history of excessive alcohol intake (median 190 g/day) for a prolonged period (median 10 years), and other causes of liver disease were excluded. Drinking controls comprised patients with repeated hospital admissions for alcohol withdrawal (the level of alcohol consumption was similar to that seen in patients with ALD) who did not show any clinical or biochemical evidence of liver disease. Non-drinking controls comprised hospital and university staff who were either teetotallers or consumed ≤21 units for males or ≤14 units for females.

Other causes of liver disease, including viral hepatitis, primary biliary cirrhosis, haemochomatosis, {alpha}-1-antitrypsin deficiency, Wilson's disease and hepatotoxic drug ingestion, were excluded in all cases. The age and gender characteristics of the cases and controls are shown in Table 2. All samples were obtained after ethical committee approval and informed consent from the participants.


View this table:
[in this window]
[in a new window]
 
Table 2. Mean age and gender distributions in ALD patients and drinking/healthy controls

 
GST genotyping
DNA was extracted from peripheral blood leucocytes using standard phenol/chloroform extraction. Genotypes were determined as follows: GSTM1 A, B, A/B and null genotypes were identified using an amplification refractory mutation system approach based on polymerase chain reaction (PCR), with allele-specific primers to exon 7 (Elexperu-Camiruaga et al., 1996Go). GSTM3 AA, AB and BB genotypes were identified using primers to exon 6/7 (Inskip et al., 1995Go). GSTP1 Ile/Ile, Ile/Val and Val/Val genotypes at amino acid 105 were identified by PCR with digestion with Alw261 to identify the A–G transition at position 1578 (Ramachandran et al., 2000Go). GSTT1 null and expressing subjects were also identified using PCR (Elexperu-Camiruaga et al., 1996Go). The GSTA1-69 alleles were identified using the method of Coles et al. (2001)Go. Since some DNA samples were refractory to amplification or were exhausted, it was not possible to obtain complete genotype data on all patients. Genotyping for GSTM1, M3 and T1 was performed on Birmingham subjects and for GSTM1, P1, T1 and A1 on Liverpool subjects. Genotyping for the Birmingham and North Staffordshire cohorts was performed in North Staffordshire whereas genotyping for Liverpool was performed in Liverpool (except for GSTA1, which was performed in North Staffordshire). The methodology for the characterization of the GSTM1-expressing genotypes was not available in Liverpool. The GSTA1 genotype was not available for the Birmingham samples owing to insufficient material.

Statistical analysis
The Stata software package (version 8, Stata Corporation, Texas) was used for all statistical analyses. Chi-squared tests were used to examine the associations between genotype frequencies and risk.


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The frequencies for GST genotypes are shown in Table 3. Hardy–Weinberg equilibrium was achieved in most groups. However, GSTM3 genotypes in the North Staffordshire healthy controls showed a significant deviation (P < 0.001), whereas GSTP1 in the North Staffordshire healthy controls (P = 0.040) and GSTA1 in the North Staffordshire (P = 0.032) and Liverpool (P = 0.041) drinking controls showed a borderline deviation from equilibrium.


View this table:
[in this window]
[in a new window]
 
Table 3. Genotype frequencies in controls and patients with Alcoholic Liver Disease

 
GSTM1
Differentiation between GSTM1-expressing genotypes was not available for the Liverpool cohort. The frequencies of the GSTM1 null genotype were similar among the healthy controls from North Staffordshire, Birmingham and Liverpool. The frequency of GSTM1 null in the drinking controls from North Staffordshire was lower than that for the corresponding healthy controls from this centre, although the number of North Staffordshire drinking controls for whom the GSTM1 genotype was available was small and failed to achieve statistical significance (, P = 0.141). GSTM1 genotypes were not significantly different among the ALD case groups from the three centres. A comparison of the control groups with the corresponding ALD cases showed no significant differences in GSTM1 genotype frequencies.

GSTM3
GSTM3 genotype data were not available for the Liverpool cohort. The frequencies of GSTM3 genotypes were similar in the control groups from North Staffordshire and Birmingham. Similarly, GSTM3 genotypes were not significantly different between the ALD cases from North Staffordshire and Birmingham. The distribution of GSTM3 genotypes was similar in the ALD cases from North Staffordshire and Birmingham and the corresponding control groups.

GSTP1
The frequencies of GSTP1 genotypes were similar in the healthy controls from North Staffordshire and Birmingham, though the distributions of genotypes between North Staffordshire and Liverpool (, P = 0.041). and between Birmingham and Liverpool (, P = 0.021), were significantly different. The distributions of GSTP1 genotypes were similar in the drinking controls from North Staffordshire and Liverpool and in the ALD cases from the three centres. No significant associations between the GSTP1 genotype susceptibility to ALD and were identified.

GSTT1
The frequencies of GSTT1 genotypes were similar in the healthy controls from North Staffordshire, Birmingham and Liverpool and in the North Staffordshire and Liverpool drinking controls. The distributions of GSTT1 genotypes were similar in the ALD cases from North Staffordshire and Liverpool, though the null genotype was significantly less common in the Birmingham ALD cases than in those from Liverpool (, P = 0.012). Comparisons of the Liverpool healthy controls with the ALD cases showed the frequency of the GSTT1 null genotype to be significantly higher in cases than in controls (, P = 0.044). However, this was not reproduced in the data from North Staffordshire or Birmingham, or between the Liverpool ALD cases and drinking controls (P = 0.161).

GSTA1
The frequencies of GSTA1 genotypes demonstrated a marked variability across all groups. Comparisons between groups from the two centres for which data were available showed differences in the healthy controls, though this failed to achieve statistical significance (, P = 0.090), in the drinking controls (, P = 0.009) and in the ALD cases (, P = 0.082). Comparisons between the ALD cases and the corresponding controls showed significant differences in genotype distributions between the North Staffordshire drinking controls and the corresponding ALD cases (, P = 0.009) and between the Liverpool ALD cases and healthy controls (, P = 0.031). However, these results were not consistent with frequencies of the GSTA1 –69 CC genotype being lower in the North Staffordshire cases than in the controls, and higher in the Liverpool ALD cases than in the controls.

Though the recruitment criteria used by the three centers were slightly different, all the ALD patients who were recruited demonstrated evidence of alcohol-related liver disease. It was therefore possible to pool data from the three centers. Pooling of data demonstrated no significant differences between the ALD cases and either control group for any of the genes studied.


    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The study did not find a definite association of GSTM1, M3, T1, P1 or A1 enzyme polymorphisms with chronic liver disease compared with drinking and non-drinking controls. It did, however, illustrate a number of the difficulties encountered in reproducing data from genetic association studies. Significant increases in GSTT1 null were found in a population of patients from Liverpool that were not confirmed in patients from North Staffordshire and Birmingham, and there were opposing differences in the frequency of GSTA1 genotypes in case–control comparisons from the Staffordshire and Liverpool cohorts.

Overall, a large number of patients (a total of 344 patients) and controls (a total of 936 patients) were studied, giving this study a potentially significant power to exclude or confirm associations. However, the divergence from Hardy–Weinberg equilibrium in some control groups, the variability in genotype frequencies in both cases and controls among the centres and the lack of reproducibility of significant associations suggest that the significant associations that were observed are likely to be false positives (type 1 errors).

Selection of controls is a perennial problem with case–control studies. We attempted to match controls by ethnic group, age, sex and level of alcohol consumption. We had difficulties in recruiting large numbers of non-drinking controls and definitively excluding liver disease in this group. We assumed that normal LFTs and absence of clinical evidence of liver disease would exclude drinkers with significant liver disease but biopsy is the only definitive way to exclude chronic liver disease, which was not often ethically indicated in this group. We were unable to recruit large numbers of drinking controls but selected non-drinking controls from the same population. This in itself presented a number of problems and we have examined a number of control sources: hospital controls, spouses of cases and health laboratory staff, all of whom have the potential for bias due to population stratification. Indeed, population stratification has been suggested to be the major cause of the alarming proportion of genetic associations studies that have failed to be replicated (Cardon and Palmer, 2003Go).

Another possible reason for the discrepancies among results from the different centres is the heterogeneity among the centres in terms of case definition (population stratification within the cases). North Staffordshire had a combination of severe and mild liver disease, Birmingham included only decompensated liver disease and the Liverpool group comprised many patients with severe liver disease. There are a variety of alcoholic liver disease manifestations clinically and histologically, and presumably pathogenically. It may be that the polymorphisms in ROS detoxifying enzymes are critical in a subtype of ALD that is more critically dependent on ROSs. Stewart et al. (2002)Go have related polymorphisms in manganese superoxide dismutase (MnSOD) to evidence of inflammation from liver biopsy. In addition, polymorphisms may be related to the outcome of chronic alcohol-related liver disease such as susceptibility to hepatocellular carcinoma (Bian et al., 2000Go). A stricter standardization of cases may reveal some significant susceptibility from GST polymorphisms and should be used to assess the possible effects of GSTT1 null and GSTA1. It is also possible that at a molecular level, ALD represents more than one disease entity, and stratification of patients based on transcriptomic profile may be needed in the future to reduce the problems of heterogeneity among cases.

It is possible that the significant associations are real and represent differences among the centres in terms of linkage disequilibrium between significant polymorphisms and neighbouring disease-associated allelic variants, or that interacting factors (environmental exposures or genetic factors) differ among the centres. Assessing the former explanation would require a more detailed haplotype study, which is not feasible given its cost relative to the probability of success. However, this explanation would not account for the lack of conformation to Hardy–Weinberg equilibrium in the controls, and has not generally been borne out in most single-report association studies. Furthermore, in our study, significant results have been identified only in a single centre, which supports the view of a false positive result.

An increase in GSTM1 null frequency in ALD has been reported once (Harada et al., 1987Go) and in another study there was an increase among patients with chronic liver disease that approached significance (Savolainen et al., 1996Go). However, this result was not found in three other studies (Groppi et al., 1991Go; Rodrigo et al., 1999Go; Frenzer et al., 2001). Interestingly, an increase in the GSTM1 null genotype has been observed in patients with primary biliary cirrhosis (Davies et al., 1993Go) and autoimmune chronic active hepatitis (Fukagawa et al., 2001Go). It may be that liver disease characterized by T-cell damage may be more critically dependent on GSTM1 activity. Our finding of an increase in the GSTT1 null genotype has not been replicated in a second group and elsewhere (Frenzer et al., 2002Go), which suggests that this observation in North Staffordshire patients is unlikely to be significant. There have been no previous studies of GSTA1.

We believe that the polymorphisms studied have functional significance (Hayes and Strange, 2000Go), though this has been questioned for GSTA1 (Bredschneider et al., 2002Go). However, it may be that the effect of polymorphisms in GSTs in determining ROS detoxification is negated, as it is now thought that hepatic glutathione is depleted by alcohol consumption (Fernandez-Checa et al., 1997Go). Furthermore, it is also possible that in situations of liver damage, GST enzymes are not expressed as there is evidence that hepatic stellate cells stop expressing GST enzymes when activated (Whalen et al., 1999Go). It is also possible that the effect of GST polymorphisms in modulating a response to oxidative stress is minimal in the presence of more powerful modifying factors such as amount of alcohol consumed and other genetic factors, or that the effect of particular polymorphisms depends on other genetic factors (epistatic interactions), as has been observed for TNF-{alpha} and ADH3 polymorphisms (Grove et al., 1998Go).

Overall, though we did identify some significant associations, this study does not support or refute the importance of ROSs in alcoholic liver injury. In summary, we have failed to identify reproducible associations with GST polymorphisms in three populations of patients with chronic alcohol-related liver disease, though it is acknowledged that there are further polymorphisms in these or other GST genes that may demonstrate significant associations.


    ACKNOWLEDGEMENTS
 
We would like to thank the West Midlands R and D (LORS), the NHS Executive North West and the Queen Elizabeth Hospital, Liver Foundation Trust for financial support.


    REFERENCES
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Arteel, G. E. (2003) Oxidants and antioxidants in alcohol-induced liver disease. Gastroenterology 124, 778–790.[CrossRef][ISI][Medline]

Becker, U., Deis, A., Sorensen, T. I., Gronbaek, M., Borch-Johnsen, K., Muller, C. F., Schnohr, P. and Jensen, G. (1996) Prediction of liver disease by alcohol intake, sex and age: a prospective population study. Hepatology 23, 1025–1029.[ISI][Medline]

Bellentani, S., Tribelli, S., Saccoccio, G., Sodde, M., Fratti, N., De Martin, C. and Cristianini, G. (1994) Prevalence of chronic liver disease in the general population of Northern Italy: the Dionysos study. Hepatology 20, 1442–1449.[ISI][Medline]

Bian, J. C., Shen, F. M., Shen, L., Wang, T. R., Wang, X. H., Chen, G. C. and Wang, J. B. (2000) Susceptibility to hepatocellular carcinoma associated with null genotypes of GSTM1 and GSTT1. World Journal of Gastroenterology 6, 228–230.[ISI][Medline]

Bredschneider, M., Klein, K., Murdter, T. E., Marx, C., Eichelbaum, M., Nussler, A. K., Neuhaus, P., Zanger, U. M. and Schwab, M. (2002) Genetic polymorphisms of glutathione S-transferase A1, the major glutathione S-transferase in human liver: consequences for enzyme expression and busulfan conjugation. Clinical Pharmacology and Therapeutics 71, 479–487.[CrossRef][ISI][Medline]

Brind, A., Fryer, A., Hurlstone, A., Fisher, N. and Pirmohamed, M. (2003) The role of polymorphism in manganese superoxide dismutase in susceptibility to alcoholic liver disease. Gastroenterology 124, 2000–2002.

Cardon, L. R., and Palmer, L. J. (2003) Population stratification and spurious allelic association. Lancet 361, 598–604.[CrossRef][ISI][Medline]

Coles, B. F., Morel, F., Rauch, C., Huber, W. W., Yang, M., Teitel, C. H., Green, B., Lang, N. P. and Kadlubar, F. F. (2001) Effect of polymorphism in the human glutathione S-transferase A1 promoter on hepatic GSTA1 and GSTA2 expression. Pharmacogenetics 11, 663–669.[CrossRef][ISI][Medline]

Davies, M. H., Elias, E., Acharya, S., Cotton, W., Faulder, G. C., Fryer, A. A. and Strange R. C. (1993) GSTM1 null polymorphism at the glutathione S-transferase M1 locus: phenotype and genotype studies in patients with primary biliary cirrhosis. Gut 34, 549–53.[Abstract]

Degoul, F., Sutton, A., Mansouri, A., Cepanec, C., Degott, C., Fromenty, B., Beaugrand, M., Valla, D. and Pessayre, D. (2001) Homozygosity for alanine in the mitochondrial targeting sequnce of superoxide dismutase and risks for sever alcoholic liver disease. Gastroenterology 120, 1468–1474.[ISI][Medline]

Elexperu-Camriuaga, J., Buxton, N., Kandula, V., Dias, P. S., Campbell, D., McIntosh, J., Broome, J., Jones, P., Inskip, A., Alldersea, J., Fryer, A. A. and Strange R. C. (1996) Susceptibility to astrocytoma and menigioma: influence of allelism at glutathione S-transferase, GSTT1 and GSTM1 and cytochrome P450, CYP2D6 loci. Cancer Research 55, 4237–4239.[ISI]

Fernandez-Checa, J. C., Kaplowitz, N., Garcia-Ruiz, C., Colell, A., Miranda, M., Mari, M., Ardite, E. and Morales, A. (1997) GSH transport in mitochondria: defence against TNF-induced oxidative stress and alcohol-induced effect. American Journal of Physiology 273, G7–17.[ISI][Medline]

Frenzer, A., Butler, W. J., Norton, I. D., Wilson, J. S., Apte, M. V., Pirola, R. C., Ryan, P., Roberts-Thomson, I. C. (2002) Polymorphism in alcohol-metabolizing enzymes, glutathione S-transferases and apolipoprotein E and susceptibility to alcohol-induced cirrhosis and chronic pancreatitis. Journal of Gastroenterology and Hepatology 17, 177–182.[CrossRef][ISI][Medline]

Fukagawa, N. K., Liang, P., Li, M., Ashikaga, T., Reddy, K. R. and Krawitt, E. L. (2001) Glutathione-S-transferase M1 null genotype in autoimmune hepatitis. Digestive Diseases Science 46, 2080–2083.[CrossRef][ISI]

Groppi, A., Coutelle, C., Fleury, B., Iron, A., Begueret, J. and Couzigou, P. (1991) Glutathione S-transferase class m in French alcoholic cirrhotic patients. Human Genetics 87, 628–30.[ISI][Medline]

Grove, J., Brown, A. S., Daly, A. K., Bassendine, M. F., James, O. F. and Day, C. P. (1998) The Rsa1 polymorphism of CYP2E1 and susceptibility to alcoholic liver disease and dependence on alcohol dehydrogenase genotype. Pharmacogenetics 8, 335–342.[ISI][Medline]

Harada, S., Agarwal, D. P. and Goedde, H. W. (1987) Aldehyde dehydrogenase and glutathione-S-transferase polymorphism: association between phenotype frequencies and alcoholism. Progress in Clinical and Biological Research 241, 241–250.[Medline]

Harrison, D. J., May, L., Hayes, P. C., Haque, M. M. and Hayes, J. D. (1990) Glutathione S-transferases in alcoholic liver disease. Gut 31, 909–912.[Abstract]

Hayes, J. D. and Strange, R. C. (2000) Glutathione S-transferase polymorphisms and their biological consequences. Pharmacology 61, 154–66.[CrossRef][ISI][Medline]

Henrion-Caude, A., Flamant, C., Roussey, M., Housset, C., Flahault, A., Fryer, A. A., Chadelat, K., Strange, R. C. and Clement, A. (2002) Liver disease in pediatric patients with cystic fibrosis is associated with glutathione S-transferase P1 polymorphism. Hepatology 36, 913–917.[ISI][Medline]

Hoek, J. B., Pastorino, J. G., Hoek, J. B. and Pastorino, J. G. (2002) Ethanol, oxidative stress, and cytokine-induced liver cell injury. Alcohol 27, 63–68.[CrossRef][ISI][Medline]

Hrubec, Z. and Omenn, G. (1981) Evidence of genetic susceptibility predisposition to alcoholic cirrhosis and psychosis: twin concordances for alcoholism and its biological end points by zygosity among male veterans. Alcoholism: Clinical and Experimental Research 5, 207–215.[ISI][Medline]

Inskip, A., Elexperu-Camiruaga, J., Buxton, N., Dias, P. S., MacIntosh, J., Campbell, D., Jones, P. W., Yengi, L., Talbot, J. A. and Strange, R. C. (1995) Identification of polymorphism at the glutathione S-transferase, GSTM3 locus: evidence for linkage with GSTM1*A. Biochemical Journal 312, 713–716.[ISI][Medline]

Mari, M. and Cederbaum, A. I. (2001) Induction of catalase, alpha, and microsomal glutathione S-transferase in CYP2E1 overexpressing HepG2 cells and protection against short-term oxidative stress. Hepatology 33, 652–661.[CrossRef][ISI][Medline]

Meagher, E. A., Barry, O. P., Burke, A., Lucey, M. R., Lawson, J. A., Rokach, J. and FitzGerald, G. A. (1999) Alcohol-induced generation of lipid peroxidation products in humans. Journal of Clinical Investigation 104, 805–813.[Abstract/Free Full Text]

Polavarapu, R., Spitz, D. R., Sim, J. E., Follansbee, M. H., Oberley, L. W., Rahemtulla, A. and Nanji, A. A. (1998) Increased lipid peroxidation and impaired antioxidant enzyme function is associated with pathological liver injury in experimental alcoholic liver disease in rats fed diets high in corn and fish oil. Hepatology 27, 1317–1323.[ISI][Medline]

Ramachandran, S., Hoban, P. R., Ichii-Jones, F., Pleasants, L., Ali-Osman, F., Lear, J. T., Smith, A. G., Bowers, B., Jones, P. W., Fryer, A. A. and Strange, R. C. (2000) Glutathione S-transferase GSTP1 and cyclin D1 genotypes: association with numbers of basal cell carcinomas in a patient subgroup at high-risk of multiple tumours. Pharmacogenetics 10, 545–56.[CrossRef][ISI][Medline]

Roman, J., Colell, A., Blasco, C., Caballeria, J., Pares, A., Rodes, J. and Fernandez-Checa, J. C. (1999) Differential role of ethanol and acetaldehyde in the induction of oxidative stress in HEP G2 cells: effect on transcription factors AP-1 and NF-kb. Hepatology 30, 1473–1480.[ISI][Medline]

Rodrigo, L., Alvarez, V., Rodriguez, M., Perez, R., Alvarez, R. and Coto, E. (1999) N-acetyltransferase-2, glutathione S-transferase M1, alcohol dehydrogenase, and cytochrome P4502E1 genotypes in alcoholic liver cirrhosis: a case–control study. Scandinavian Journal of Gastroenterology 34, 303–307.[CrossRef][ISI][Medline]

Savolainen, V. T., Pjarinen, J., Perola, M., Penttila, A. and Karhunen, P. J. (1996) Glutathione-S-transferase GST M1 ‘null’ genotype and the risk of alcoholic liver disease. Alcoholism: Clinical and Experimental Research 20, 1340–1345.[ISI][Medline]

Stewart, S. F., Leathart, J. B., Chen, Y., Daly, A. K., Rolla, R., Vay, D., Mottaran, E., Vidali, M., Albano, E. and Day, C. P. (2002) Valine-alanine manganese superoxide dismutase polymorphism is not associated with alcohol-induced oxidative stress or liver fibrosis. Hepatology 36, 1355–1360.[CrossRef][ISI][Medline]

Tsukamoto, H., Rippe, R., Niemela, O. and Lin, M. (1995) Roles of oxidative stress in activation of Kupffer and Ito cells in liver fibrogenesis. Journal of Gastroenterology and Hepatology 10 (Suppl. 1), S50–53.[ISI][Medline]

Whalen, R., Rockey, D. C., Friedman, S. L. and Boyer, T. D. (1999) Activation of rat hepatic stellate cells leads to loss of glutathione S-transferases and their enzymatic activity against products of oxidative stress. Hepatology 30, 927–933.[ISI][Medline]





This Article
Abstract
Full Text (PDF)
Alert me when this article is cited
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in ISI Web of Science
Similar articles in PubMed
Alert me to new issues of the journal
Add to My Personal Archive
Download to citation manager
Request Permissions
Google Scholar
Articles by BRIND, A. M.
Articles by FRYER, A. A.
PubMed
PubMed Citation
Articles by BRIND, A. M.
Articles by FRYER, A. A.