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Activation of Cyp2E1 leads to Oxidative Stress
Key Event Relationship Overview
AOPs Referencing Relationship
Life Stage Applicability
Key Event Relationship Description
Cyp2E1 activation has two major outcomes: (1) the production of reactive, electrophilic metabolites, and (2) a significant increase in the half-life of the Cyp2E1 enzyme (Gonzalez 2007, Song, et al. 1989). The former is important because metabolites can go on to produce cellular damage by reacting with cellular nucleophiles. The latter is important because the Cyp2E1 catalytic cycle is prone to uncoupling (i.e., instead of incorporating an oxygen atom in to the substrate, the catalytic cycle is interrupted because a superoxide radical is released), which results in the release of reactive oxygen species (ROS) and an increase in cellular oxidative stress (Lieber 1999).
Evidence Collection Strategy
Evidence Supporting this KER
It is well known that uncoupling of Cyp2E1 catalytic cycle results in the release of harmful reactive oxygen species in the cell (Lieber 1999).
Oxidative stress is produced during chronic activation (and uncoupling) of the Cyp2E1 catalytic cycle. The cytochrome P-450 catalytic cycle is known to undergo uncoupling leading to the production of ROS (Gorsky, et al. 1984, Loida and Sligar 1993, Meunier, et al. 2004). If this uncoupling occurs, a molecule of superoxide radical is released, which has the effect of interrupting the P450 catalytic cycle and releasing harmful ROS into the cell. Typically superoxide is converted to hydrogen peroxide (H2O2) by superoxide dismutase (SOD), which is further reduced into the hydroxyl radical (OH•), and then to water. Other relevant cellular antioxidants include glutathione, thioredoxin, and peroxiredoxins. However, it is also possible for these ROS to scavenge electrons from cellular macromolecules (proteins, lipids, nucleic acids). Because Cyp2E1 is membrane-bound, ROS most commonly react with lipids and initiate lipid peroxidation. Further, Cyp2E1 can undergo NADPH-dependent ‘futile cycling’, which produces ROS and contributes to the occurrence of lipid peroxidation (Ekstrom and Ingelman-Sundberg 1989). The cellular sources and effects of ROS, as well as the corresponding enzymes and antioxidants are have been thoroughly reviewed (Nakazawa, et al. 1996).
Uncertainties and Inconsistencies
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Caro, A.A., Cederbaum, A.I., 2004. Oxidative stress, toxicology, and pharmacology of CYP2E1. Annu. Rev. Pharmacol. Toxicol. 44, 27-42.
Ekstrom, G., Ingelman-Sundberg, M., 1989. Rat liver microsomal NADPH-supported oxidase activity and lipid peroxidation dependent on ethanol-inducible cytochrome P-450 (P-450IIE1). Biochem. Pharmacol. 38, 1313-1319.
Gonzalez, F.J., 2007. The 2006 Bernard B. Brodie Award Lecture. Cyp2e1. Drug metabolism and disposition: the biological fate of chemicals 35, 1-8.
Gorsky, L.D., Koop, D.R., Coon, M.J., 1984. On the stoichiometry of the oxidase and monooxygenase reactions catalyzed by liver microsomal cytochrome P-450. Products of oxygen reduction. J. Biol. Chem. 259, 6812-6817.
Jackson, A.F., Williams, A., Recio, L., Waters, M.D., Lambert, I.B., Yauk, C.L., 2014. Case study on the utility of hepatic global gene expression profiling in the risk assessment of the carcinogen furan. Toxicol. Appl. Pharmacol. 274, 63-77.
Kessova, I.G., Ho, Y.S., Thung, S., Cederbaum, A.I., 2003. Alcohol-induced liver injury in mice lacking Cu, Zn-superoxide dismutase. Hepatology 38, 1136-1145.
Lieber, C.S., 1999. Microsomal ethanol-oxidizing system (MEOS): The first 30 years (1968- 1998) - A review. Alcohol. Clin. Exp. Res. 23, 991-1007.
Lu, Y., Cederbaum, A.I., 2008. CYP2E1 and oxidative liver injury by alcohol. Free Radical Biology and Medicine 44, 723-738.
Lu, Y., Wu, D., Wang, X., Ward, S.C., Cederbaum, A.I., 2010. Chronic alcohol-induced liver injury and oxidant stress are decreased in cytochrome P4502E1 knockout mice and restored in humanized cytochrome P4502E1 knock-in mice. Free Radic. Biol. Med. 49, 1406-1416.
Meunier, B., de Visser, S.P., Shaik, S., 2004. Mechanism of oxidation reactions catalyzed by cytochrome p450 enzymes. Chem. Rev. 104, 3947-3980.
Nakazawa, H., Genka, C., Fujishima, M., 1996. Pathological aspects of active oxygens/free radicals. Jpn. J. Physiol. 46, 15-32.
Nanji, A.A., Zhao, S., Sadrzadeh, S.M., Dannenberg, A.J., Tahan, S.R., Waxman, D.J., 1994. Markedly enhanced cytochrome P450 2E1 induction and lipid peroxidation is associated with severe liver injury in fish oil-ethanol-fed rats. Alcohol. Clin. Exp. Res. 18, 1280-1285.
Song, B.J., Veech, R.L., Park, S.S., Gelboin, H.V., Gonzalez, F.J., 1989. Induction of rat hepatic N-nitrosodimethylamine demethylase by acetone is due to protein stabilization. J. Biol. Chem. 264, 3568-3572.
Tindberg, N., Ingelman-Sundberg, M., 1989. Cytochrome P-450 and oxygen toxicity. Oxygen-dependent induction of ethanol-inducible cytochrome P-450 (IIE1) in rat liver and lung. Biochemistry 28, 4499-4504.
Yang, L., Wu, D., Wang, X., Cederbaum, A.I., 2011. Depletion of cytosolic or mitochondrial thioredoxin increases CYP2E1-induced oxidative stress via an ASK-1-JNK1 pathway in HepG2 cells. Free Radic. Biol. Med. 51, 185-196.