* Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas;
Center for Basic Research in Digestive Diseases, Mayo Clinic, Rochester, Minnesota;
Department of Biochemistry and Molecular Biology, Mount Sinai School of Medicine, New York, New York;
INSERM, Hôpital Beaujon, Clichy, France; and
¶ Department of Cell and Developmental Biology, Room 236 Taylor Hall, University of North Carolina, Chapel Hill, North Carolina 27599
Received June 20, 2001; accepted October 15, 2001
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ABSTRACT |
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Key Words: bile acids; cytochrome P4502E1; cholestasis; Kupffer cells; microvesicular steatosis; mitochondrial permeability transition; neutrophils; nitric oxide; oxidative stress; peroxynitrite.
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INTRODUCTION |
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The liver synthesizes, concentrates, and secretes bile acids and excretes other toxicants, such as bilirubin. Drug-induced injury to hepatocytes and bile duct cells can lead to cholestasis. Cholestasis, in turn, causes intrahepatic accumulation of toxic bile acids and excretion products, which promotes further hepatic injury. Fortunately, the liver has enormous regenerative capacity, but regeneration of hepatocytes lost by necrotic and apoptotic cell death may mask detection of drug-induced injury. Furthermore, the active proliferative response of hepatocytes makes the liver an important target of carcinogens.
Hepatic nonparenchymal cells, the Kupffer, sinusoidal endothelial, and stellate (fat-storing or Ito) cells, and newly recruited leukocytes, i.e., monocytes and neutrophils, also contribute to the pathogenesis of hepatic toxicity. Kupffer cells and neutrophils are a source of proinflammatory cytokines and chemokines and of reactive oxygen and nitrogen species, which promote oxidative stress in injury induced by toxicants and ischemia/reperfusion. Kupffer cells also play a key role in hepatic injury due to ethanol consumption. The uniquely fenestrated sinusoidal endothelial cell is selectively vulnerable to cold ischemia/reperfusion injury to cause graft failure after transplantation and to cancer chemotherapy agents to cause veno-occlusive disease. Activated stellate cells synthesize collagen whose overproduction leads to hepatic fibrosis and cirrhosis.
The goal of this brief review is to discuss new developments in our understanding of the mechanisms of liver toxicity from drugs and other xenobiotics in the context of hepatic physiology, metabolism, and cell biology. The sections that follow emphasize important injury mechanisms, which can be a consequence of metabolism and/or direct cell toxicity of chemicals. These mechanisms include bile acid-induced liver cell injury during cholestasis, pathophysiological effects of mitochondrial dysfunction, and cell damage by reactive oxygen and nitrogen species. The importance of vascular (Kupffer cells, neutrophils) and intracellular generation of reactive oxygen by mitochondria and xenobiotic-inducible enzymes (e.g., CYP 4502E1) will be discussed.
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Bile Acid-Induced Hepatocyte Apoptosis |
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In cultured rat hepatocytes, the hydrophobic bile acid glycochenodeoxycholate, GCDC, at pathophysiologically relevant concentrations (20100 µM) induces apoptosis, as documented by cell shrinkage, nuclear condensation and lobulation, caspase activation, DNA fragmentation, and phosphatidylserine externalization (Patel et al., 1994). Thus, bile acids provide a valuable model to dissect the mechanisms of liver cell apoptosis and the role of apoptosis in liver injury from endogenous toxicants.
Apoptosis occurs by one of two pathways: (1) a death-receptor pathway, and (2) the mitochondrial pathway (Green, 1998). To determine if death-receptor pathways contribute to bile acid-mediated apoptosis, hepatocytes from tumor necrosis factor-receptor 1 (TNF-R1) and Fas-deficient mice were exposed to GCDC. TNF-R1 and Fas are the predominant death receptors expressed by hepatocytes (Faubion and Gores, 1999
). Hepatocytes from Fas-deficient lpr mice were resistant to GCDC-mediated apoptosis, whereas TNF-R1-deficient hepatocytes readily underwent apoptosis. Unexpectedly, hepatocytes from Fas ligand-deficient mice were also sensitive to GCDC-stimulated apoptosis (Faubion et al., 1999
). These data implicate ligand-independent Fas-mediated apoptosis as a contributing mechanism for bile acid-related liver injury. To further test this concept, the bile ducts of wild type and Fas-deficient mice were ligated to produce severe extrahepatic cholestasis. Caspase 8, an initiator cysteine-aspartate protease in apoptosis, was activated in wild type animals but not Fas-deficient mice. Bile duct ligated Fas-deficient animals also had less apoptosis, decreased liver injury, and improved survival as compared to wild type mice (Miyoshi et al., 1999
). Thus, Fas activation appears to play a dominant role in bile acid cytotoxicity.
How do bile acids cause Fas activation? Potential mechanisms include alterations in Fas synthesis, Fas compartmentation, and Fas trimerization in the plasma membrane. However, toxic bile acids did not increase Fas synthesis. Rather, bile acids promoted rapid transport of cytoplasmic vesicular Fas to the plasma membrane in a microtubule-dependent manner (Sodeman et al., 2000). Bile acid-induced apoptosis was dependent upon this translocation of Fas to the plasma membrane. Whether Fas translocation is sufficient to trigger spontaneous association of Fas receptor death domains is unclear. Nonetheless, toxicant-induced transport of intracellular death receptors to the plasma membrane is a new paradigm for cell death. In summary, bile acids accumulate in the liver when canalicular transport is impaired, which results in translocation of cytoplasmic Fas to the plasma membrane where these receptors self-aggregate and trigger cell death by apoptosis (Fig. 1
).
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Adhesion Molecules and Oxidant Stress in Inflammatory Liver Injury |
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Previous work during the last 10 years characterized a role for neutrophils in the pathophysiology of inflammatory liver injury, and many aspects that are relevant for neutrophil-mediated cytotoxicity also apply to mononuclear cells. Neutrophils can be recruited into the hepatic vasculature by local tissue injury and CXC chemokine generation (Lawson et al., 2000b; Maher et al., 1997
) or the systemic exposure to inflammatory mediators, including tumor necrosis factor-
(TNF-
), IL-1, complement factors, platelet activating factor, and CXC chemokines (Jaeschke, 1997
). Each of these mediators upregulates ß2 integrins on neutrophils (Jaeschke, 1997
). In liver, neutrophils accumulate in sinusoids and adhere to venular endothelial cells (Chosay et al., 1997
). In general, recruitment of neutrophils into sinusoids does not depend on cellular adhesion molecules (CAMs; Jaeschke, 1997
) but appears to result from mechanical trapping due to rheological changes in neutrophils, active vasoconstriction in sinusoids and swelling of the sinusoidal lining cells (Jaeschke, 1997
). However, subsequent steps of firm adhesion to endothelial cells, transmigration and adherence to hepatocytes are dependent on CAMs, including ICAM-1 and VCAM-1 (Essani et al., 1995
,1997
). Expression of E-selectin on endothelial cells activates neutrophils during transmigration (Lawson et al., 2000a
). Neutrophil adhesion and extravasation in sinusoids do not involve PECAM-1 or P- or L-selectin. In contrast, neutrophil rolling and adhesion in postsinusoidal venules are dependent on P- and L-selectin and ICAM-1, respectively (Jaeschke, 1997
; Lawson et al., 2000a
). CAMs are differentially expressed and are cytokine-inducible on all liver cell types (Jaeschke, 1997
). On leukocytes, members of the ß2-(CD18)-integrin family are critical for neutrophil-mediated injury (Jaeschke et al., 1993
). LFA-1 (CD11a/CD18) and Mac-1 (CD11b/CD18) are involved in transmigration and adhesion to hepatocytes (Jaeschke and Smith, 1997
). Upregulation of Mac-1 is a prerequisite for neutrophil cytotoxicity (Jaeschke et al., 1993
). Adherence of neutrophils to target cells through Mac-1 triggers release of proteases and prolonged reactive oxygen formation. Neutrophils are rarely cytotoxic when present in sinusoids and must transmigrate into the subsinusoidal space to cause tissue injury (Chosay et al., 1997
). In order to transmigrate and attack, neutrophils must receive a chemotactic signal. CXC chemokines generated by hepatocytes can trigger a neutrophil-induced injury (Maher et al., 1997
). Furthermore, lipid peroxidation products are highly chemotactic (Curzio et al., 1986
) and may be responsible for the continuation and amplification of the injury (Liu et al., 1994
). Recently, apoptotic cell death of hepatocytes was identified as a potent stimulus for neutrophil extravasation and enhancement of endotoxin-induced injury (Jaeschke et al., 1998
; Lawson et al., 1998
). In human alcoholic hepatitis, apoptotic hepatocytes colocalize with neutrophils, which correlates strongly with the severity of tissue damage (Ziol et al., 2001
). Thus, hepatocyte apoptosis and neutrophil extravasation may be important events in alcoholic liver injury.
Despite the improved understanding of neutrophil-mediated hepatotoxicity, the molecular mechanism of cell death remains controversial (Jaeschke, 2000). In vitro studies using neutrophil-hepatocyte cocultures have identified proteases as the critical mediators of cell injury (Jaeschke et al., 1996
; Jaeschke and Smith, 1997
). In support of this concept, protease inhibitors attenuate neutrophil hepatotoxicity in vivo (Jaeschke and Smith, 1997
). Recent data also suggest that neutrophil-derived reactive oxygen species can induce an intracellular oxidant stress in hepatocytes that triggers necrotic cell injury in less than 1 h (Jaeschke et al., 1999
). Similar results can be obtained with a macrophage-derived oxidant stress in the liver (Bilzer et al., 1999
). The mechanism of injury does not involve gross lipid peroxidation (Jaeschke et al., 1999
) but may be caused by the opening of the membrane permeability transition pore and the collapse of the mitochondrial membrane potential (Nieminen et al., 1995
). In addition to causing cell injury, reactive oxygen species promote inflammation by enhancing the activation of the transcription factor NF-
B, which controls the formation of cytokines, chemokines, and adhesion molecules (Jaeschke, 2000
).
In summary, drug toxicity, tissue trauma, ischemia-reperfusion, sepsis, and other pathophysiological events activate both neutrophils and Kupffer cells directly or through activation of complement (Fig. 2). Kupffer cells release cytotoxic mediators, such as reactive oxygen species, and proinflammatory mediators, such as cytokines and chemokines. Complement factors (e.g., C5a) and cytokines prime and activate neutrophils to promote their recruitment into the hepatic vasculature. If chemotactically stimulated, neutrophils extravasate and adhere to parenchymal cells, which induces necrotic cell death through release of reactive oxygen and proteases. Adhesion molecules on neutrophils (ß2 integrins, especially CD11b/CD18) and ICAM-1 on endothelial cells and hepatocytes are essential for neutrophil margination, extravasation, and oxidant production. Cytokines can induce hepatic adhesion molecule and chemokine formation, which in turn is modulated by oxidant stress. The growing insight into mechanisms of neutrophil cytotoxicity in vivo should lead to new therapeutic strategies to prevent neutrophil-induced tissue injury without paralyzing host-defense functions.
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CYP2E1-Dependent Toxicity in HepG2 Cells |
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An approach to understand the effects and actions of CYP2E1 is to express human CYP2E1 in cell lines. CYP2E1 overexpressing HepG2 cell lines were established by retroviral infection methods (E9 cells) and by plasmid transfection methods (E47 cells; Chen and Cederbaum, 1998; Dai et al., 1993
). E9 and E47 cells express CYP2E1 at levels of about 10 and 45 pmol/mg microsomal protein, respectively. Compounds actively metabolized by CYP2E1 to reactive intermediates, such as acetaminophen or carbon tetrachloride, were toxic to CYP2E1-overexpressing HepG2 cells but not to control cells, which validates the model for study of CYP2E1-dependent toxicity (Dai and Cederbaum, 1995a
,b
).
Ethanol, iron, and polyunsaturated fatty acids, such as arachidonic acid (but not monoenoic acids such as oleic acid), were considerably more toxic to CYP2E1-overexpressing E9 cells than MV5 control cells (Chen et al., 1997; Sakurai and Cederbaum, 1998
; Wu and Cederbaum, 1996
). Toxicity was concentration- and time-dependent and associated with lipid peroxidation. Antioxidants, especially inhibitors of lipid peroxidation, prevented toxicity. The toxicity correlated with CYP2E1 levels and was enhanced after transfection with a sense CYP2E1 plasmid and diminished after transfection with an antisense CYP2E1 plasmid. CYP2E1-dependent cell killing was apoptotic, associated with activation of caspase 3 (a major effector caspase in apoptosis), and blocked by pancaspase inhibition (Chen et al., 1997
; Sakurai and Cederbaum, 1998
; Wu and Cederbaum, 1999
). Bcl-2 is a proto-oncogene that blocks cytochrome c release during apoptotic signaling through mitochondria, and transfection with a plasmid containing Bcl-2 prevented the apoptosis, implicating a mitochondrial pathway for apoptosis (Chen et al., 1997
). Iron and arachidonic acid decreased mitochondrial membrane potential in the CYP2E1-overexpressing cells and lowered cellular ATP levels. HepG2 cells were also infected with adenoviruses containing catalase cDNA and catalase cDNA directed to mitochondria by the 27-amino acid peptide leader sequence of manganese superoxide dismutase. Both catalase constructs protected CYP2E1-overexpressing E47 cells against iron and arachidonic acid toxicity (Bai and Cederbaum, 2001
).
Glutathione (GSH) is a critical cellular antioxidant. After GSH depletion with buthionine sulfoximine (BSO), the toxicity of ethanol, iron, arachidonic acid, and acetaminophen was strikingly enhanced (Chen and Cederbaum, 1998; Chen et al., 1997
; Sakurai and Cederbaum, 1998
; Wu and Cederbaum, 1996
,1999
). BSO treatment of CYP2E1-overexpressing E47 cells caused toxicity even in the absence of an added toxicant (Chen and Cederbaum, 1998
). CYP2E1 inhibitors and antioxidants prevented cell killing, which was partly apoptotic and partly necrotic. Surprisingly, GSH in E47 cells was increased compared to C34, E9, and MV control cells. Increased GSH represented increased GSH synthesis due to transcriptional activation of the gamma-glutamyl cysteinyl synthase gene and was blocked by antioxidants (Mari and Cederbaum, 2000
). Activity, protein, and mRNA levels for other antioxidant enzymes, such as catalase,
- and microsomal glutathione transferases, were also increased in E47 cells (Mari and Cederbaum, 2001
). Upregulation of these antioxidant genes may reflect an adaptive mechanism to detoxify CYP2E1-derived oxidants.
Hepatic stellate cells are central to the fibrotic response of the liver to injury, and ROS activate stellate cells (Friedman, 2000). Since CYP2E1 produces ROS, ethanol-induced CYP2E1 expression may promote collagen type I biosynthesis by stellate cells. However, CYP2E1 is mostly present in hepatocytes, whereas stellate cells contain low levels of CYP2E1. Accordingly, a coculture model involving HepG2 cells and stellate cells was developed (Mari et al., 2001
, Nieto et al., manuscript in preparation). A time-dependent increase in collagen type I was observed when stellate cells were coincubated with C34 control cells, which was further elevated when stellate cells were coincubated with CYP2E1-overexpressing E47 cells. However, little type I collagen was released into the incubation medium from the C34 plus stellate cell coculture. By contrast, E47 plus stellate cell cocultures secreted much more type I collagen protein. These experiments suggest that CYP2E1-overexpressing E47 cells generate diffusible mediators that promote type I collagen synthesis and release by stellate cells. Catalase and vitamin E markedly decreased type I collagen synthesis by both cocultures and completely blocked the increased collagen production by the E47 coculture. These results suggest that E47 cells release ROS, such as H2O2 and lipid peroxidation products, that stimulate type I collagen synthesis by stellate cells.
HepG2 cells expressing CYP2E1 have proven to be a valuable model to characterize the biochemical and toxicological properties of CYP2E1. Induction of CYP2E1 by ethanol appears to be one of the central pathways by which ethanol generates a state of oxidative stress. Figure 3 depicts a working hypothesis of the role of CYP2E1 in ethanol-induced oxidative stress and hepatotoxicity. While several mechanisms likely contribute to alcohol-induced liver injury, the linkage between CYP2E1-dependent oxidative stress, mitochondrial injury, and increased collagen formation by stellate cells may make an important mechanistic contribution to the toxic action of ethanol on the liver.
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Peroxynitrite in Drug-Induced Hepatotoxicity |
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Recent work shows that nitrated tyrosine occurs in hepatic centrilobular cells. These adducts colocalize in cells containing the acetaminophen-protein adducts (Hinson et al., 2000,1998
). Peroxynitrite, a highly reactive nitrating and oxidizing species formed by the rapid reaction of nitric oxide (NO) and superoxide, produces nitrated tyrosine (Beckman, 1996
; Pryor and Squadrito, 1995
). Since acetaminophen-protein adducts correlate with development of necrosis (Hart et al., 1995
; Roberts et al., 1991
), it follows that nitration of tyrosine correlates with necrosis.
Recent evidence suggests that activated Kupffer cells are mechanistically important in NO and superoxide formation. Pretreatment of rats and mice with macrophage inactivators (gadolinium chloride, dextran sulfate, LPS, or dichloromethylene diphosphonate) dramatically decreased acetaminophen toxicity (Blazka et al., 1995; Goldin et al., 1996
; Laskin et al., 1995
; Laskin and Pendino, 1995
; Michael et al., 1999
; Winwood and Arthur, 1993
). Neither gadolinium chloride nor dextran sulfate decreased acetaminophen protein binding, but both decreased nitration of tyrosine (Michael et al., 1999
). However, other cellular sources of NO and superoxide may be important. Hepatocytes and stellate cells express inducible nitric oxide synthase (iNOS; Muriel, 2000
), and acetaminophen induces iNOS in rat hepatocytes (Gardner et al., 1998
). Endothelial cells constitutively express eNOS (Muriel, 2000
). Various sources produce superoxide, including damaged mitochondria (Knight et al., 2001
).
The importance of iNOS in acetaminophen toxicity was investigated by utilizing iNOS knockout mice (Michael et al., 2001). Although serum ALT levels (a biomarker of liver toxicity) was less in iNOS knockout mice than in wild type mice after acetaminophen treatment, histology showed no significant differences in hepatotoxicity. Acetaminophen induced an approximate 5-fold induction of NO synthesis (serum nitrate plus nitrite) in wild type mice, and the increase in serum nitrate plus nitrite paralleled increases in serum ALT. Increased NO synthesis was not observed in iNOS knockout mice, although a small increase in nitrotyrosine residues was observed. Nitrotyrosine in the knockout mice was in centrilobular areas, which suggested involvement of constitutively expressed NOS. Consistent with previously reported data, acetaminophen did not increase lipid peroxidation in wild type mice (Kamiyama et al., 1993
). By contrast, hepatic lipid peroxidation (malondialdehyde) increased in iNOS knockout mice (Michael et al., 2001
).
It is hypothesized that the initial step in acetaminophen toxicity is metabolism to NAPQI, leading to depletion of GSH and covalent adduct formation, as previously proposed. In wild type mice, induction of NO synthesis and superoxide generation occurs subsequently, leading to peroxynitrite formation. Ordinarily, GSH detoxifies peroxynitrite (Sies et al., 1997). However, after GSH depletion by NAPQI, peroxynitrite nitrates protein tyrosine and may oxidize other macromolecules. In vitro acetaminophen competes with tyrosine for reaction with peroxynitrite, but in vivo peroxynitrite reacts rapidly with protein tyrosine in wild type mice. In iNOS knockout mice, superoxide increases after acetaminophen but not NO synthesis. Superoxide then causes lipid peroxidation. Thus acetaminophen toxicity may be mediated by nitration in wild type mice and by lipid peroxidation in iNOS knockout mice (Fig. 4
). Indeed, by reacting with superoxide NO may prevent lipid peroxidation in wild type mice (Rubbo et al., 1994
).
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Hepatotoxicity Due to Mitochondrial Dysfunction |
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Microvesicular steatosis is the histological hallmark of severe metabolic perturbations causing energy shortage. Inhibition of ß-oxidation itself deprives cells of their most important source of energy during fasting. Furthermore, NEFAs and their dicarboxylic acid metabolites directly impair mitochondrial energy production (Fromenty and Pessayre, 1995). Finally, disruption of hepatic mitochondrial ß-oxidation decreases delivery of hepatic ketone bodies and glucose to peripheral tissues (Fromenty and Pessayre, 1995
). The resulting deficiency of energy substrates may cause renal failure, pancreatitis, coma, and death (Fromenty and Pessayre, 1995
).
Damage to mitochondrial DNA (mtDNA) and direct inhibition of mitochondrial respiration also inhibit ß-oxidation (Fromenty and Pessayre, 1995). ß-Oxidation consumes NAD+ and transforms it into NADH. Mitochondrial respiration reoxidizes NADH into the NAD+ that is required for ß-oxidation. Therefore, impairment of respiration inhibits ß-oxidation. Thus, various endogenous and exogenous substances impair mitochondrial ß-oxidation to cause microvesicular steatosis through different mechanisms. Oxidative stress after ethanol causes damage to mitochondrial proteins, lipids, and DNA. mtDNA depletion occurs in ethanol-treated mice (Mansouri et al., 1999
). In humans, these oxidative lesions cause mtDNA deletions (Mansouri et al., 1997
). Interferon-
and nucleoside analogs (dideoxynucleosides, fialuridine) impair mtDNA transcription and replication, respectively (Lewis and Dalakas, 1995
; Shan et al., 1990
). DNA polymerase
incorporates nucleoside reverse transcriptase inhibitors into mtDNA, an event that blocks mtDNA replication, eventually causing mtDNA depletion.
Salicylic acid and valproic acid sequester CoA, which is needed to form thio esters with fatty acids (Deschamps et al., 1991; Kesterson et al., 1984
). 2,4-Diene-valproyl-CoA, a reactive metabolite of valproic acid, may also inactivate ß-oxidation enzymes (Kassahun and Abbott, 1993
). Several drugs inhibit ß-oxidation, including tetracycline derivatives (Labbe et al., 1991
), glucocorticoids (Lettéron et al., 1997
), the nonsteroidal antiinflammatory drugs ibuprofen and pirprofen (Fréneaux et al., 1990
; Genève et al., 1987
), the antidepressant drugs amineptine and tianeptine (Fromenty et al., 1989
; Le Dinh et al., 1988
), the antianginal cationic amphiphilic drugs amiodarone, perhexiline, and diethylaminoethoxyhexestrol (Berson et al., 1998
; Deschamps et al., 1994
; Fromenty et al., 1990
), as well as female sex hormones or pregnancy (Grimbert et al., 1993
).
These metabolic effects may combine to block mitochondrial ß-oxidation and trigger microvesicular steatosis. For example, Reye's syndrome occurs after a viral infection in children taking aspirin and/or having a latent inborn defect in ß-oxidation enzymes (Fromenty and Pessayre, 1995). Likewise, acute fatty liver of pregnancy is more frequent in women whose fetus has a genetic deficiency in long-chain 3-hydroxy-acyl-CoA dehydrogenase (Ibdah et al., 1999
).
Nonalcoholic steatohepatitis (NASH).
NASH develops progressively in patients with chronic, macrovacuolar, or microvesicular steatosis, leading to liver cell death, Mallory bodies, polynuclear cell infiltrates, fibrosis, and cirrhosis (Pessayre et al., 2001). NASH occurs in patients with the obesity/hypertriglyceridemia/insulin resistance syndrome, or can be induced by chronic amiodarone, perhexiline, or diethylaminoethoxyhexestrol administration (Pessayre et al., 2001
). These cationic amphiphilic drugs concentrate electrophoretically into mitochondria to inhibit ß-oxidation and respiration (Berson et al., 1998
). Respiratory inhibition leads to ROS formation by mitochondria to cause lipid peroxidation of fat deposits (Berson et al., 1998
). Similarly in alcohol abuse, increased ROS formation causes lipid peroxidation and steatohepatitis (Pessayre et al., 2001
). Both lipid peroxidation and ROS-induced cytokine release (TGF-ß, TNF-
, IL-8) may contribute to the development of NASH (Pessayre et al., 2001
).
Cytolytic hepatitis.
Cytolytic hepatitis is a severe liver lesion that can cause liver failure and may involve mitochondrial uncoupling or respiratory inhibition (Berson et al., 1996,2001
). Another mechanism is onset of the mitochondrial permeability transition (MPT) caused by opening of permeability transition (PT) pores in the mitochondrial inner membrane. PT pore opening causes mitochondrial depolarization, uncoupling, and large amplitude swelling and can lead to both necrotic and apoptotic cell death (Lemasters et al., 1998
; Pessayre et al., 1999
). PT pore opening in all mitochondria of a cell causes ATP depletion, which prevents apoptosis (an energy-requiring process) and causes necrosis (Lemasters et al., 1999; Pessayre et al., 1999
). In contrast, PT pore opening in only some mitochondria permits ATP synthesis by the unaffected mitochondria, thus preventing necrosis. In mitochondria undergoing the MPT, however, matrix swelling and outer membrane rupture causes release of mitochondrial cytochrome c, which activates caspases in the cytosol to cause apoptosis (Bradham et al., 1998
; Feldmann et al., 2000
; Hatano et al., 2000
).
Drugs cause the MPT through diverse mechanisms. Some compounds, such as ROS (Nieminen et al., 1995), thio crosslinkers, bile acids (Botla et al., 1995
), atractyloside (Halestrap and Davidson, 1990
), betulinic acid (Fulda et al., 1998
), and lonidamide (Ravagnan et al., 1999
), may directly induce PT pore opening, whereas other drugs, such as salicylic acid and valproic acid, may facilitate PT pore opening by calcium (Lemasters et al., 1998
). Other drugs, such as anticancer drugs, cause Fas ligand expression in hepatocytes to initiate Fas- and MPT-dependent fratricidal killing (Müller et al., 1997
).
The most frequent mechanism of cytolytic hepatitis is cytochrome P450-dependent formation of reactive metabolites that cause direct toxicity or immune reactions. Reactive metabolites may cause DNA damage and overexpression of p53 and Bax, as well as glutathione depletion, protein thiol oxidation, and increased cytosolic Ca2+ (Haouzi et al., 2000). Bax overexpression, disulfide formation, and increased mitochondrial Ca2+ all promote MPT and cell death (Haouzi et al., 2000
). Covalent binding of reactive metabolites to hepatic proteins can also trigger an immune response. Cytotoxic T lymphocytes kill their targets by 3 mechanisms: cell surface Fas ligand expression, formation of TNF-
, and release of granzyme B (Pessayre et al., 1999
). All 3 events trigger the MPT to cause death of target cells (Bradham et al., 1998
; Feldmann et al., 2000
; Hatano et al., 2000
; Pessayre et al., 1999
).
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CONCLUSION |
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ACKNOWLEDGMENTS |
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NOTES |
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This article is based on a symposium entitled "Mechanisms of Hepatotoxicity" presented at the 40th annual meeting of the Society of Toxicology, March 2001, San Francisco, CA.
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