TY - JOUR
T1 - Induction or inhibition of cytochrome P450 2E1 modiWes the acute toxicity of acrylonitrile in rats
T2 - Biochemical evidence
AU - Suhua, Wang
AU - Rongzhu, Lu
AU - Wenrong, Xu
AU - Guangwei, Xing
AU - Xiaowu, Zhao
AU - Shizhong, Wang
AU - Ye, Zhang
AU - Fangan, Han
AU - Aschner, Michael
N1 - Funding Information:
Acknowledgments We are grateful to Dr. Jordi Llorens (University of Barcelona, Spain), Prof. Arthur I. Cederbaum (Mount Sinai School of Medicine, USA) and Prof Peter Spencer (Oregon Health & Science University, USA) for their critical comments and editing. This work was supported in part by the Natural Science Foundation of Jiangsu Province (No. BK 20040061 to Lu Rongzhu), the Social Development Foundation of Jiangsu Province (No. BS 2005049 to Han Fangan and Lu Rongzhu), the Natural Science Foundation of China (No. 30872139 to Lu Rongzhu), SCI-TECH (No. 2008-018-02 to Xu Wenrong), the Nutrition-Disease Team Fund of Jiangsu University (to Lu Rongzhu) and the National Institute of Environmental Health Sciences (No. ES07331 to Michael Aschner).
PY - 2010/6
Y1 - 2010/6
N2 - The present study was designed to examine the eVects 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 signiWcantly 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 signiWcantly 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 signiWcantly higher than those in AN-treated rats. Brain lipid peroxidation was enhanced, and the antioxidant capacity was signiWcantly 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 oVer further emergency medication.
AB - The present study was designed to examine the eVects 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 signiWcantly 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 signiWcantly 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 signiWcantly higher than those in AN-treated rats. Brain lipid peroxidation was enhanced, and the antioxidant capacity was signiWcantly 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 oVer further emergency medication.
KW - Acrylonitrile
KW - CYP2E1
KW - Cyanide
KW - Cytochrome c oxidase
KW - Oxidative stress
KW - Toxicity
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U2 - 10.1007/s00204-010-0519-7
DO - 10.1007/s00204-010-0519-7
M3 - Article
C2 - 20127315
AN - SCOPUS:77953026084
SN - 0340-5761
VL - 84
SP - 461
EP - 469
JO - Archives of Toxicology
JF - Archives of Toxicology
IS - 6
ER -