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Chronic ethanol feeding potentiates Fas Jo2-induced hepatotoxicity: role of CYP2E1 and TNF-alpha and activation of JNK and P38 MAP kinase.
Free Radic Biol Med. 2009 Sep 01; 47(5):518-28.FR

Abstract

We have previously shown that treatment of mice with pyrazole or acute ethanol potentiated Fas agonistic Jo2 antibody-induced liver injury by a mechanism involving induction of CYP2E1 and elevated oxidative stress. The current study evaluated whether chronic alcohol feeding potentiates Fas-induced liver injury and whether CYP2E1 plays a role in any enhanced hepatotoxicity. Wild-type and CYP2E1 knockout mice were fed ethanol or isocaloric dextrose for 4 weeks followed by a single treatment with either saline or Jo2. Mice were killed 8 h after the Jo2 challenge. There were three- to five fold increases in transaminases and more extensive eosinophilic necrosis, hemorrhage, and infiltration of inflammatory cells in the central zone of the hepatic lobule in the ethanol-fed mice treated with Jo2 compared to the dextrose/Jo2- or ethanol/saline-treated mice. Liver injury was blunted in ethanol-fed CYP2E1 knockout mice treated with Jo2. The chronic ethanol feeding produced steatosis, elevation of CYP2E1, and oxidative stress in wild-type but not CYP2E1 knockout mice. These changes in wild-type mice fed ethanol were similar after saline or Jo2 treatment. The Jo2 treatment produced activation of JNK and P38 MAP kinase, increased activity of caspase-8 and -3, and lowered hepatic GSH levels in both the dextrose- and the alcohol-fed mice. JNK was activated at early times after Jo2 treatment in the ethanol-fed mice. Serum TNF-alpha levels were strikingly elevated in the wild-type ethanol/Jo2 group, which showed liver injury, compared to all the other groups, which did not show liver injury. Inhibition of JNK or P38 MAPK partially, but not completely, prevented the elevated liver injury in the wild-type ethanol/Jo2 mice. These results show that chronic ethanol feeding enhances Fas-induced liver injury by a mechanism associated with induction of CYP2E1, elevated serum TNF-alpha levels, and activation of MAPK.

Authors+Show Affiliations

Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, NY 10029, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

19477265

Citation

Wang, Xiaodong, et al. "Chronic Ethanol Feeding Potentiates Fas Jo2-induced Hepatotoxicity: Role of CYP2E1 and TNF-alpha and Activation of JNK and P38 MAP Kinase." Free Radical Biology & Medicine, vol. 47, no. 5, 2009, pp. 518-28.
Wang X, Lu Y, Xie B, et al. Chronic ethanol feeding potentiates Fas Jo2-induced hepatotoxicity: role of CYP2E1 and TNF-alpha and activation of JNK and P38 MAP kinase. Free Radic Biol Med. 2009;47(5):518-28.
Wang, X., Lu, Y., Xie, B., & Cederbaum, A. I. (2009). Chronic ethanol feeding potentiates Fas Jo2-induced hepatotoxicity: role of CYP2E1 and TNF-alpha and activation of JNK and P38 MAP kinase. Free Radical Biology & Medicine, 47(5), 518-28. https://doi.org/10.1016/j.freeradbiomed.2009.05.021
Wang X, et al. Chronic Ethanol Feeding Potentiates Fas Jo2-induced Hepatotoxicity: Role of CYP2E1 and TNF-alpha and Activation of JNK and P38 MAP Kinase. Free Radic Biol Med. 2009 Sep 1;47(5):518-28. PubMed PMID: 19477265.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Chronic ethanol feeding potentiates Fas Jo2-induced hepatotoxicity: role of CYP2E1 and TNF-alpha and activation of JNK and P38 MAP kinase. AU - Wang,Xiaodong, AU - Lu,Yongke, AU - Xie,Bin, AU - Cederbaum,Arthur I, Y1 - 2009/05/27/ PY - 2009/03/09/received PY - 2009/05/05/revised PY - 2009/05/16/accepted PY - 2009/5/30/entrez PY - 2009/5/30/pubmed PY - 2009/12/16/medline SP - 518 EP - 28 JF - Free radical biology & medicine JO - Free Radic Biol Med VL - 47 IS - 5 N2 - We have previously shown that treatment of mice with pyrazole or acute ethanol potentiated Fas agonistic Jo2 antibody-induced liver injury by a mechanism involving induction of CYP2E1 and elevated oxidative stress. The current study evaluated whether chronic alcohol feeding potentiates Fas-induced liver injury and whether CYP2E1 plays a role in any enhanced hepatotoxicity. Wild-type and CYP2E1 knockout mice were fed ethanol or isocaloric dextrose for 4 weeks followed by a single treatment with either saline or Jo2. Mice were killed 8 h after the Jo2 challenge. There were three- to five fold increases in transaminases and more extensive eosinophilic necrosis, hemorrhage, and infiltration of inflammatory cells in the central zone of the hepatic lobule in the ethanol-fed mice treated with Jo2 compared to the dextrose/Jo2- or ethanol/saline-treated mice. Liver injury was blunted in ethanol-fed CYP2E1 knockout mice treated with Jo2. The chronic ethanol feeding produced steatosis, elevation of CYP2E1, and oxidative stress in wild-type but not CYP2E1 knockout mice. These changes in wild-type mice fed ethanol were similar after saline or Jo2 treatment. The Jo2 treatment produced activation of JNK and P38 MAP kinase, increased activity of caspase-8 and -3, and lowered hepatic GSH levels in both the dextrose- and the alcohol-fed mice. JNK was activated at early times after Jo2 treatment in the ethanol-fed mice. Serum TNF-alpha levels were strikingly elevated in the wild-type ethanol/Jo2 group, which showed liver injury, compared to all the other groups, which did not show liver injury. Inhibition of JNK or P38 MAPK partially, but not completely, prevented the elevated liver injury in the wild-type ethanol/Jo2 mice. These results show that chronic ethanol feeding enhances Fas-induced liver injury by a mechanism associated with induction of CYP2E1, elevated serum TNF-alpha levels, and activation of MAPK. SN - 1873-4596 UR - https://www.unboundmedicine.com/medline/citation/19477265/Chronic_ethanol_feeding_potentiates_Fas_Jo2_induced_hepatotoxicity:_role_of_CYP2E1_and_TNF_alpha_and_activation_of_JNK_and_P38_MAP_kinase_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0891-5849(09)00315-3 DB - PRIME DP - Unbound Medicine ER -