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Role of CYP2E1 in ethanol-induced oxidant stress, fatty liver and hepatotoxicity.
Dig Dis. 2010; 28(6):802-11.DD

Abstract

BACKGROUND/AIMS

Several pathways contribute to mechanisms by which ethanol induces oxidant stress. While some studies support a role for cytochrome P450 2E1 (CYP2E1), others do not. There is a need to develop oral models of significant ethanol-induced liver injury and to evaluate the possible role of CYP2E1 in ethanol actions in such models.

METHODS

We evaluated chronic ethanol-induced liver injury, steatosis and oxidant stress in wild-type (WT) mice, CYP2E1 knockout (KO) mice and in humanized CYP2E1 knockin (KI) mice, where the human 2E1 was added back to mice deficient in the mouse 2E1. WT mice and CYP2E1 KO and KI mice (both provided by Dr. F. Gonzalez, NCI) were fed a high-fat Lieber-DeCarli liquid diet for 3 weeks; pair-fed controls received dextrose.

RESULTS

Ethanol produced fatty liver and oxidant stress in WT mice, but liver injury (transaminases, histopathology) was minimal. Ethanol-induced steatosis and oxidant stress were blunted in the KO mice (no liver injury) but restored in the KI mice. Significant liver injury was produced in the ethanol-fed KI mice with elevated transaminases and necrosis. This liver injury in the KI mice was associated with elevated oxidant stress and elevated levels of the human CYP2E1 compared to levels of the mouse 2E1 in WT mice. Activation of JNK was observed in the ethanol-fed KI mice compared to the other groups. Fatty liver in WT and KI mice was associated with lower levels of lipolytic PPAR-α. No such changes were found in the ethanol-fed KO mice.

CONCLUSIONS

These results show that CYP2E1 plays a major role in ethanol-induced fatty liver and oxidant stress. Restoring CYP2E1 in the CYP2E1 KO mice restores ethanol-induced fatty liver and oxidant stress.

Authors+Show Affiliations

Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, N.Y., USA. arthur.cederbaum@mssm.edu

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

21525766

Citation

Cederbaum, Arthur I.. "Role of CYP2E1 in Ethanol-induced Oxidant Stress, Fatty Liver and Hepatotoxicity." Digestive Diseases (Basel, Switzerland), vol. 28, no. 6, 2010, pp. 802-11.
Cederbaum AI. Role of CYP2E1 in ethanol-induced oxidant stress, fatty liver and hepatotoxicity. Dig Dis. 2010;28(6):802-11.
Cederbaum, A. I. (2010). Role of CYP2E1 in ethanol-induced oxidant stress, fatty liver and hepatotoxicity. Digestive Diseases (Basel, Switzerland), 28(6), 802-11. https://doi.org/10.1159/000324289
Cederbaum AI. Role of CYP2E1 in Ethanol-induced Oxidant Stress, Fatty Liver and Hepatotoxicity. Dig Dis. 2010;28(6):802-11. PubMed PMID: 21525766.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Role of CYP2E1 in ethanol-induced oxidant stress, fatty liver and hepatotoxicity. A1 - Cederbaum,Arthur I, Y1 - 2011/04/27/ PY - 2011/4/29/entrez PY - 2010/1/1/pubmed PY - 2011/8/25/medline SP - 802 EP - 11 JF - Digestive diseases (Basel, Switzerland) JO - Dig Dis VL - 28 IS - 6 N2 - BACKGROUND/AIMS: Several pathways contribute to mechanisms by which ethanol induces oxidant stress. While some studies support a role for cytochrome P450 2E1 (CYP2E1), others do not. There is a need to develop oral models of significant ethanol-induced liver injury and to evaluate the possible role of CYP2E1 in ethanol actions in such models. METHODS: We evaluated chronic ethanol-induced liver injury, steatosis and oxidant stress in wild-type (WT) mice, CYP2E1 knockout (KO) mice and in humanized CYP2E1 knockin (KI) mice, where the human 2E1 was added back to mice deficient in the mouse 2E1. WT mice and CYP2E1 KO and KI mice (both provided by Dr. F. Gonzalez, NCI) were fed a high-fat Lieber-DeCarli liquid diet for 3 weeks; pair-fed controls received dextrose. RESULTS: Ethanol produced fatty liver and oxidant stress in WT mice, but liver injury (transaminases, histopathology) was minimal. Ethanol-induced steatosis and oxidant stress were blunted in the KO mice (no liver injury) but restored in the KI mice. Significant liver injury was produced in the ethanol-fed KI mice with elevated transaminases and necrosis. This liver injury in the KI mice was associated with elevated oxidant stress and elevated levels of the human CYP2E1 compared to levels of the mouse 2E1 in WT mice. Activation of JNK was observed in the ethanol-fed KI mice compared to the other groups. Fatty liver in WT and KI mice was associated with lower levels of lipolytic PPAR-α. No such changes were found in the ethanol-fed KO mice. CONCLUSIONS: These results show that CYP2E1 plays a major role in ethanol-induced fatty liver and oxidant stress. Restoring CYP2E1 in the CYP2E1 KO mice restores ethanol-induced fatty liver and oxidant stress. SN - 1421-9875 UR - https://www.unboundmedicine.com/medline/citation/21525766/Role_of_CYP2E1_in_ethanol_induced_oxidant_stress_fatty_liver_and_hepatotoxicity_ L2 - https://www.karger.com?DOI=10.1159/000324289 DB - PRIME DP - Unbound Medicine ER -