Fasting Enhances the Acute Toxicity of Acrylonitrile in Mice via Induction of CYP2E1
Suhua Wang,
Guangwei Xing,
Fang Li,
Bobo Yang,
Yu Zhang,
Michael Aschner,
Rongzhu Lu
Affiliations
Suhua Wang
Department of Preventive Medicine and Public Health Laboratory Science, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang 212013, China
Guangwei Xing
Department of Preventive Medicine and Public Health Laboratory Science, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang 212013, China
Fang Li
Department of Preventive Medicine and Public Health Laboratory Science, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang 212013, China
Bobo Yang
Department of Preventive Medicine and Public Health Laboratory Science, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang 212013, China
Yu Zhang
Department of Preventive Medicine and Public Health Laboratory Science, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang 212013, China
Michael Aschner
Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
Rongzhu Lu
Department of Preventive Medicine and Public Health Laboratory Science, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang 212013, China
Cytochrome P450 2E1 (CYP2E1) plays an essential role in the susceptibility to acute acrylonitrile (AN)-induced toxicity. Here, we investigated the toxicity and mechanism of AN in fasting mice and potential underlying mechanisms. Convulsions, loss of righting reflex, and death 4 h after AN treatment were observed and recorded for each group of mice. Relative to ad lib-fed mice, 48 h fasting significantly increased the acute toxicity of AN, as noted by a more rapid onset of convulsions and death. In addition, fasting significantly enhanced CYP2E1-mediated oxidative metabolism of AN, resulting in increased formation of CN- (one of the end-metabolites of AN). Moreover, fasting decreased hepatic GSH content, abrogating the detoxification of GSH. However, trans-1,2-dichloroethylene (DCE), a CYP2E1 inhibitor, altered the level of hepatic CYP2E1 activity in response to fasting, reduced the acute toxic symptoms of AN and the content of CN- in AN-treated mice. These data establish that fasting predisposes to AN toxicity, attributable to induced CYP2E1 and reduced hepatic GSH.
