Induction or inhibition of cytochrome P450 2E1 modifies the acute toxicity of acrylonitrile in rats: biochemical evidence.
The present study was designed to examine the effects of the inhibition or induction of CYP2E1 activity on acute acrylonitrile (AN) toxicity in rats. Increased or decreased hepatic CYP2E1 activity was achieved by pretreatment with acetone or trans-1,2-dichloroethylene (DCE), respectively. AN (50 mg/kg) was administered by intraperitoneal injection. Onset of convulsions and death were observed in rats with increased CYP2E1 activity, whereas convulsions and death did not appear in rats within 1 h after treatment with AN alone. Convulsions occurred in all AN-treated animals with increased CYP2E1 activity at approximately 18 min. The levels of cyanide (CN(-)), a terminal metabolite of AN, were significantly increased in the brains and livers of the AN-treated rats with increased CYP2E1 activity, compared with the levels in rats treated with AN alone, DCE + AN or acetone + DCE + AN. The cytochrome c oxidase (CcOx) activities in the brains and livers of the rats treated with AN or AN + acetone were significantly lower than those in the normal control rats and the rats treated with DCE, whereas the CcOx activities in the brains and livers of rats with decreased CYP2E1 activity were significantly higher than those in AN-treated rats. Brain lipid peroxidation was enhanced, and the antioxidant capacity was significantly compromised in rats with decreased CYP2E1 activity compared with rats with normal or increased CYP2E1 activity. Therefore, inhibition of CYP2E1 and simultaneous antioxidant therapy should be considered as supplementary therapeutic interventions in acute AN intoxication cases with higher CYP2E1 activity, thus a longer window of opportunity would be got to offer further emergency medication.
Suhua
Wang
W
Department of Preventive Medicine, School of Medical Science and Laboratory Medicine, Jiangsu University, 301 Xuefu Rd, Zhenjiang, Jiangsu, 212013, China.
Rongzhu
Lu
L
Wenrong
Xu
X
Guangwei
Xing
X
Xiaowu
Zhao
Z
Shizhong
Wang
W
Ye
Zhang
Z
Fangan
Han
H
Aschner
Michael
M
D000096:Acetone / Q000494:pharmacology; D000181:Acrylonitrile / Q000633:toxicity*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002273:Carcinogens / Q000633:toxicity*; D003486:Cyanides / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000096:biosynthesis*; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D004000:Dichloroethylenes / Q000494:pharmacology; D004347:Drug Interactions; D003576:Electron Transport Complex IV / Q000378:metabolism; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008136:Longevity / Q000187:drug effects; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced
D002273:Carcinogens; D003486:Cyanides; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D004000:Dichloroethylenes; D004791:Enzyme Inhibitors; D000096:Acetone; D019392:Cytochrome P-450 CYP2E1; D003576:Electron Transport Complex IV; D000181:Acrylonitrile; C035384:1,2-dichloroethylene