Issue 4, 2013

Chronic ethanol and high glucose inducible CYP2E1 mediated oxidative stress leads to greater cellular injury in VL-17A cells: a potential mechanism for liver injury due to chronic alcohol consumption and hyperglycemia

Abstract

Diabetes, characterized by the presence of inherent oxidative stress, may be further complicated by the additional oxidative stress generated due to the metabolism of alcohol. This study focuses on the roles of alcohol and high glucose inducible ADH and CYP2E1, both of which function as ethanol metabolizing enzymes, in promoting oxidative stress and cellular damage under chronic alcohol plus hyperglycemic conditions in VL-17A cells over-expressing ADH and CYP2E1. A specific CYP2E1 inhibitor, diallyl sulfide, proved to be more effective in decreasing the toxicity in VL-17A cells exposed to chronic alcohol plus high glucose than the specific ADH inhibitor pyrazole and the dual ADH and CYP2E1 inhibitor 4-methyl pyrazole. Furthermore, the greatest decrease in several parameters for oxidative stress such as ROS level, lipid peroxidation, protein carbonyl and protein aldehyde adduct formation and apoptosis was observed in the diallyl sulfide plus chronic alcohol plus high glucose treated VL-17A cells. In addition, specific inhibition of CYP2E1 with phenethyl isothiocyanate or CYP2E1 siRNA led to significant restoration of viability, and decrease in oxidative stress and apoptosis. Thus, the inducibility of CYP2E1 with both ethanol and high glucose leads to greater oxidative stress and cellular dysfunction in liver.

Graphical abstract: Chronic ethanol and high glucose inducible CYP2E1 mediated oxidative stress leads to greater cellular injury in VL-17A cells: a potential mechanism for liver injury due to chronic alcohol consumption and hyperglycemia

Article information

Article type
Paper
Submitted
23 Nov 2012
Accepted
03 Mar 2013
First published
11 Apr 2013

Toxicol. Res., 2013,2, 245-258

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