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Activation of Cyp2E1 leads to Hepatocytotoxicity
Key Event Relationship Overview
AOPs Referencing Relationship
|Rodentia sp.||Rodentia sp.||High||NCBI|
Life Stage Applicability
|All life stages||High|
Key Event Relationship Description
Metabolism of xenobiotics by cytochrome P450 mono-oxygenases produces reactive metabolites. Under normal circumstances, these metabolites immediately become conjugated to molecules like glutathione or glucuronic acid, which facilitates their excretion. However, these metabolites can react with off-target cellular molecules, which in extreme cases (e.g., at toxic doses or following glutathione depletion during periods of oxidative stress) cause damage that results in hepatotoxicity. Typically, the unmetabolised Cyp2E1 substrates are inert, whereas their metabolites are highly cytotoxic; e.g., furan and its metabolite cis-2-butene-1,4-dial (BDA); ethanol (EtOH) and acetaldehyde; carbon tetrachloride and trichloromethyl radical (which forms the trichloromethyl peroxy radical); and, chloroform and phosgene. Lipid peroxidation in the context of Cyp2E1 has been reviewed (Caro and Cederbaum 2004). Moreover, chronic exposure to Cyp2E1 agonists depletes of conjugating enzymes and diminishes capacity to deal with reactive metabolites in the cell.
Evidence Collection Strategy
Evidence Supporting this KER
Strong. Metabolite-dependent toxicity and adduct formation are well known side-effects of cytochrome P450 mono-oxygenase metabolism of xenobiotics in the liver. Because primary metabolites are more reactive than the parent compound, they often create adducts to cellular proteins or DNA. In both cases, this prevents the normal functioning of the molecules. In extreme cases this will lead to hepatocytotoxicity due to: (1) the large number of adducts, (2) the loss of function of important cellular proteins and the related cellular processes, and (3) the loss of function of important genes due to DNA damage and mutation.
Uncertainties and Inconsistencies
While the prevailing opinion in the literature is that the toxicity of these metabolites is the result of non-genotoxic mechanisms, there are studies that argue in favour of direct genotoxic effects. It is widely thought that any observed genotoxicity is actually ‘indirect’ and is the product of oxidative stress.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Bechtold, M.M., Gee, D.L., Bruenner, U., Tappel, A.L., 1982. Carbon tetrachloride-mediated expiration of pentane and chloroform by the intact rat: the effects of pretreatment with diethyl maleate, SKF-525A and phenobarbital. Toxicol. Lett. 11, 165-171.
Brown, B.R.,Jr, Sipes, I.G., Sagalyn, A.M., 1974. Mechanisms of acute hepatic toxicity: chloroform, halothane, and glutathione. Anesthesiology 41, 554-561.
Caro, A.A., Cederbaum, A.I., 2004. Oxidative stress, toxicology, and pharmacology of CYP2E1. Annu. Rev. Pharmacol. Toxicol. 44, 27-42.
Fabrizi, L., Taylor, G.W., Edwards, R.J., Boobis, A.R., 2001. Adducts of the chloroform metabolite phosgene. Adv. Exp. Med. Biol. 500, 129-132.
Fransson-Steen, R., Goldsworthy, T.L., Kedderis, G.L., Maronpot, R.R., 1997. Furan-induced liver cell proliferation and apoptosis in female B6C3F1 mice. Toxicology 118, 195-204.
Kellert, M., Brink, A., Richter, I., Schlatter, J., Lutz, W.K., 2008. Tests for genotoxicity and mutagenicity of furan and its metabolite cis-2-butene-1,4-dial in L5178Y tk+/- mouse lymphoma cells. Mutation research 657, 127-32.
Larson, J.L., Wolf, D.C., Butterworth, B.E., 1994. Induced cytolethality and regenerative cell proliferation in the livers and kidneys of male B6C3F1 mice given chloroform by gavage. Fundamental and applied toxicology : official journal of the Society of Toxicology 23, 537-43.
Letteron, P., Labbe, G., Degott, C., Berson, A., Fromenty, B., Delaforge, M., Larrey, D., Pessayre, D., 1990. Mechanism for the protective effects of silymarin against carbon tetrachloride-induced lipid peroxidation and hepatotoxicity in mice. Evidence that silymarin acts both as an inhibitor of metabolic activation and as a chain-breaking antioxidant. Biochem. Pharmacol. 39, 2027-2034.
Martinez, M., Mourelle, M., Muriel, P., 1995. Protective effect of colchicine on acute liver damage induced by CCl4. Role of cytochrome P-450. J. Appl. Toxicol. 15, 49-52.
Moser, G.J., Foley, J., Burnett, M., Goldsworthy, T.L., Maronpot, R., 2009. Furan-induced dose–response relationships for liver cytotoxicity, cell proliferation, and tumorigenicity (furan-induced liver tumorigenicity). Experimental and Toxicologic Pathology 61, 101-111.
Park, W.J., Kim, S.Y., Kim, Y.R., Park, J.W., 2016. Bortezomib alleviates drug-induced liver injury by regulating CYP2E1 gene transcription. Int. J. Mol. Med. 37, 613-622.
Stevens, J.L., Anders, M.W., 1981. Effect of cysteine, diethyl maleate, and phenobarbital treatments on the hepatotoxicity of [1H]chloroform. Chem. Biol. Interact. 37, 207-217.
Takahashi, S., Takahashi, T., Mizobuchi, S., Matsumi, M., Morita, K., Miyazaki, M., Namba, M., Akagi, R., Hirakawa, M., 2002. Increased cytotoxicity of carbon tetrachloride in a human hepatoma cell line overexpressing cytochrome P450 2E1. J. Int. Med. Res. 30, 400-405.