Toxicological Sciences 65, 166-176 (2002)
Copyright © 2002 by the Society of Toxicology
FORUM |
Mechanisms of Hepatotoxicity
* 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
This review addresses recent advances in specific mechanisms of hepatotoxicity. Because of its unique metabolism and relationship to the gastrointestinal tract, the liver is an important target of the toxicity of drugs, xenobiotics, and oxidative stress. In cholestatic disease, endogenously generated bile acids produce hepatocellular apoptosis by stimulating Fas translocation from the cytoplasm to the plasma membrane where self-aggregation occurs to trigger apoptosis. Kupffer cell activation and neutrophil infiltration extend toxic injury. Kupffer cells release reactive oxygen species (ROS), cytokines, and chemokines, which induce neutrophil extravasation and activation. The liver expresses many cytochrome P450 isoforms, including ethanol-induced CYP2E1. CYP2E1 generates ROS, activates many toxicologically important substrates, and may be the central pathway by which ethanol causes oxidative stress. In acetaminophen toxicity, nitric oxide (NO) scavenges superoxide to produce peroxynitrite, which then causes protein nitration and tissue injury. In inducible nitric oxide synthase (iNOS) knockout mice, nitration is prevented, but unscavenged superoxide production then causes toxic lipid peroxidation to occur instead. Microvesicular steatosis, nonalcoholic steatohepatitis (NASH), and cytolytic hepatitis involve mitochondrial dysfunction, including impairment of mitochondrial fatty acid ß-oxidation, inhibition of mitochondrial respiration, and damage to mitochondrial DNA. Induction of the mitochondrial permeability transition (MPT) is another mechanism causing mitochondrial failure, which can lead to necrosis from ATP depletion or caspase-dependent apoptosis if ATP depletion does not occur fully. Because of such diverse mechanisms, hepatotoxicity remains a major reason for drug withdrawal from pharmaceutical development and clinical use.
Key Words: bile acids; cytochrome P4502E1; cholestasis; Kupffer cells; microvesicular steatosis; mitochondrial permeability transition; neutrophils; nitric oxide; oxidative stress; peroxynitrite.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  X. Deng, J. P. Luyendyk, P. E. Ganey, and R. A. Roth Inflammatory Stress and Idiosyncratic Hepatotoxicity: Hints from Animal Models Pharmacol. Rev., September 1, 2009; 61(3): 262 - 282. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Kong, J. P. Luyendyk, O. Tawfik, and G. L. Guo Farnesoid X Receptor Deficiency Induces Nonalcoholic Steatohepatitis in Low-Density Lipoprotein Receptor-Knockout Mice Fed a High-Fat Diet J. Pharmacol. Exp. Ther., January 1, 2009; 328(1): 116 - 122. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. M. Shonsey, S. M. Eliuk, M. S. Johnson, S. Barnes, C. N. Falany, V. M. Darley-Usmar, and M. B. Renfrow Inactivation of human liver bile acid CoA:amino acid N-acyltransferase by the electrophilic lipid, 4-hydroxynonenal J. Lipid Res., February 1, 2008; 49(2): 282 - 294. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. K. Venugopal, J. Chen, Y. Zhang, D. Clemens, A. Follenzi, and M. A. Zern Role of MAPK Phosphatase-1 in Sustained Activation of JNK during Ethanol-induced Apoptosis in Hepatocyte-like VL-17A Cells J. Biol. Chem., November 2, 2007; 282(44): 31900 - 31908. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Nioi, B. K. Perry, E.-J. Wang, Y.-Z. Gu, and R. D. Snyder In Vitro Detection of Drug-Induced Phospholipidosis Using Gene Expression and Fluorescent Phospholipid Based Methodologies Toxicol. Sci., September 1, 2007; 99(1): 162 - 173. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. E. Wesche-Soldato, C.-S. Chung, S. H. Gregory, T. P. Salazar-Mather, C. A. Ayala, and A. Ayala CD8+ T Cells Promote Inflammation and Apoptosis in the Liver after Sepsis: Role of Fas-FasL Am. J. Pathol., July 1, 2007; 171(1): 87 - 96. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Wullaert, G. van Loo, K. Heyninck, and R. Beyaert Hepatic Tumor Necrosis Factor Signaling and Nuclear Factor-{kappa}B: Effects on Liver Homeostasis and Beyond Endocr. Rev., June 1, 2007; 28(4): 365 - 386. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. M. Korashy, A. Shayeganpour, D. R. Brocks, and A. O.S. El-Kadi Induction of Cytochrome P450 1A1 by Ketoconazole and Itraconazole but not Fluconazole in Murine and Human Hepatoma Cell Lines Toxicol. Sci., May 1, 2007; 97(1): 32 - 43. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. K. Pacyniak, X. Cheng, M. L. Cunningham, K. Crofton, C. D. Klaassen, and G. L. Guo The Flame Retardants, Polybrominated Diphenyl Ethers, Are Pregnane X Receptor Activators Toxicol. Sci., May 1, 2007; 97(1): 94 - 102. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 U. Rauen, T. Li, I. Ioannidis, and H. de Groot Nitric oxide increases toxicity of hydrogen peroxide against rat liver endothelial cells and hepatocytes by inhibition of hydrogen peroxide degradation Am J Physiol Cell Physiol, April 1, 2007; 292(4): C1440 - C1449. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. P. O'Hara, A. J. Small, J. B. Nelson, A. D. Badley, X.-M. Chen, G. J. Gores, and N. F. LaRusso The Human Immunodeficiency Virus Type 1 Tat Protein Enhances Cryptosporidium parvum-Induced Apoptosis in Cholangiocytes via a Fas Ligand-Dependent Mechanism Infect. Immun., February 1, 2007; 75(2): 684 - 696. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Botta, S. Shi, C. C. White, M. J. Dabrowski, C. L. Keener, S. L. Srinouanprachanh, F. M. Farin, C. B. Ware, W. C. Ladiges, R. H. Pierce, et al. Acetaminophen-induced Liver Injury Is Attenuated in Male Glutamate-cysteine Ligase Transgenic Mice J. Biol. Chem., September 29, 2006; 281(39): 28865 - 28875. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. S. Kil, S. W. Shin, H. S. Yeo, Y. S. Lee, and J.-W. Park Mitochondrial NADP+-Dependent Isocitrate Dehydrogenase Protects Cadmium-Induced Apoptosis Mol. Pharmacol., September 1, 2006; 70(3): 1053 - 1061. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C.-H. Wang, Y.-C. Shen, J.-J. Hsieh, K.-Y. Yeh, and J. W.-C. Chang Clodronate alleviates cachexia and prolongs survival in nude mice xenografted with an anaplastic thyroid carcinoma cell line. J. Endocrinol., August 1, 2006; 190(2): 415 - 423. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Kezic, F. Calkoen, M. A. Wenker, J. J. Jacobs, and M. M Verberk Genetic polymorphism of metabolic enzymes modifies the risk of chronic solvent-induced encephalopathy Toxicology and Industrial Health, August 1, 2006; 22(7): 281 - 289. [Abstract] [PDF]
|
|
|
|
|
|
A. Isakovic, Z. Markovic, B. Todorovic-Markovic, N. Nikolic, S. Vranjes-Djuric, M. Mirkovic, M. Dramicanin, L. Harhaji, N. Raicevic, Z. Nikolic, et al. Distinct Cytotoxic Mechanisms of Pristine versus Hydroxylated Fullerene Toxicol. Sci., May 1, 2006; 91(1): 173 - 183. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Jaeschke and M. L. Bajt Intracellular Signaling Mechanisms of Acetaminophen-Induced Liver Cell Death Toxicol. Sci., January 1, 2006; 89(1): 31 - 41. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Titos, J. Claria, A. Planaguma, M. Lopez-Parra, A. Gonzalez-Periz, J. Gaya, R. Miquel, V. Arroyo, and J. Rodes Inhibition of 5-lipoxygenase-activating protein abrogates experimental liver injury: role of Kupffer cells J. Leukoc. Biol., October 1, 2005; 78(4): 871 - 878. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Reinehr, S. Becker, A. Eberle, S. Grether-Beck, and D. Haussinger Involvement of NADPH Oxidase Isoforms and Src Family Kinases in CD95-dependent Hepatocyte Apoptosis J. Biol. Chem., July 22, 2005; 280(29): 27179 - 27194. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. J. Lelliott, M. Lopez, R. K. Curtis, N. Parker, M. Laudes, G. Yeo, M. Jimenez-Linan, J. Grosse, A. K. Saha, D. Wiggins, et al. Transcript and metabolite analysis of the effects of tamoxifen in rat liver reveals inhibition of fatty acid synthesis in the presence of hepatic steatosis FASEB J, July 1, 2005; 19(9): 1108 - 1119. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Berasain, E. R. Garcia-Trevijano, J. Castillo, E. Erroba, M. Santamaria, D. C. Lee, J. Prieto, and M. A. Avila Novel Role for Amphiregulin in Protection from Liver Injury J. Biol. Chem., May 13, 2005; 280(19): 19012 - 19020. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W.-W. Jiang, B. Masayesva, M. Zahurak, A. L. Carvalho, E. Rosenbaum, E. Mambo, S. Zhou, K. Minhas, N. Benoit, W. H. Westra, et al. Increased Mitochondrial DNA Content in Saliva Associated with Head and Neck Cancer Clin. Cancer Res., April 1, 2005; 11(7): 2486 - 2491. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. S. Kil and J.-W. Park Regulation of Mitochondrial NADP+-dependent Isocitrate Dehydrogenase Activity by Glutathionylation J. Biol. Chem., March 18, 2005; 280(11): 10846 - 10854. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Xu, L. Chen, L. Leung, T. S. B. Yen, C. Lee, and J. Y. Chan Liver-specific inactivation of the Nrf1 gene in adult mouse leads to nonalcoholic steatohepatitis and hepatic neoplasia PNAS, March 15, 2005; 102(11): 4120 - 4125. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. W. Allen, S. R. Khetani, and S. N. Bhatia In Vitro Zonation and Toxicity in a Hepatocyte Bioreactor Toxicol. Sci., March 1, 2005; 84(1): 110 - 119. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. Teufelhofer, W. Parzefall, E. Kainzbauer, F. Ferk, C. Freiler, S. Knasmuller, L. Elbling, R. Thurman, and R. Schulte-Hermann Superoxide generation from Kupffer cells contributes to hepatocarcinogenesis: studies on NADPH oxidase knockout mice Carcinogenesis, February 1, 2005; 26(2): 319 - 329. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. Cullen Mechanistic Classification of Liver Injury Toxicol Pathol, January 1, 2005; 33(1): 6 - 8. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Venkatraman, A. Landar, A. J. Davis, L. Chamlee, T. Sanderson, H. Kim, G. Page, M. Pompilius, S. Ballinger, V. Darley-Usmar, et al. Modification of the Mitochondrial Proteome in Response to the Stress of Ethanol-dependent Hepatotoxicity J. Biol. Chem., May 21, 2004; 279(21): 22092 - 22101. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Yahagi, H. Shimano, T. Matsuzaka, M. Sekiya, Y. Najima, S. Okazaki, H. Okazaki, Y. Tamura, Y. Iizuka, N. Inoue, et al. p53 Involvement in the Pathogenesis of Fatty Liver Disease J. Biol. Chem., May 14, 2004; 279(20): 20571 - 20575. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. A. Jolly, R. Ciurlionis, D. Morfitt, M. Helgren, R. Patterson, R. G. Ulrich, and J. F. Waring Microvesicular Steatosis Induced by a Short Chain Fatty Acid: Effects on Mitochondrial Function and Correlation with Gene Expression Toxicol Pathol, February 1, 2004; 32(2_suppl): 19 - 25. [Abstract] [PDF]
|
|
|
|
|
|
J. H. Lee, E. S. Yang, and J.-W. Park Inactivation of NADP+-dependent Isocitrate Dehydrogenase by Peroxynitrite: IMPLICATIONS FOR CYTOTOXICITY AND ALCOHOL-INDUCED LIVER INJURY J. Biol. Chem., December 19, 2003; 278(51): 51360 - 51371. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. E. Nagy Recent Insights into the Role of the Innate Immune System in the Development of Alcoholic Liver Disease Experimental Biology and Medicine, September 1, 2003; 228(8): 882 - 890. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Akhgari, M. Abdollahi, A. Kebryaeezadeh, R. Hosseini, and O. Sabzevari Biochemical evidence for free radicalinduced lipid peroxidation as a mechanism for subchronic toxicity of malathion in blood and liver of rats Human and Experimental Toxicology, April 1, 2003; 22(4): 205 - 211. [Abstract] [PDF]
|
|
|
|
|
|
F. E. Mingatto, T. Rodrigues, A. A. Pigoso, S. A. Uyemura, C. Curti, and A. C. Santos The Critical Role of Mitochondrial Energetic Impairment in the Toxicity of Nimesulide to Hepatocytes J. Pharmacol. Exp. Ther., November 1, 2002; 303(2): 601 - 607. [Abstract] [Full Text] [PDF]
|
|