Resistance to carbon tetrachloride-induced hepatotoxicity in mice which lack CYP2E1 expression

被引:202
作者
Wong, FWY [1 ]
Chan, WY
Lee, SST
机构
[1] Chinese Univ Hong Kong, Dept Biochem, Shatin, New Territories, Peoples R China
[2] Chinese Univ Hong Kong, Dept Anat, Shatin, New Territories, Peoples R China
关键词
D O I
10.1006/taap.1998.8547
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
CYP2E1 knockout mice (cyp2e1(-/-)) were used to investigate the involvement of CYP2E1 in the development of carbon tetrachloride (CCl4)-induced hepatotoxicity. Male cyp2e1(-/-) and wildtype (cyp2e1(+/+)) mice were given a single ip injection of 1 ml/kg (=1.59 g/kg) CCl4 and 24 h later liver injury was assessed by elevations of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities and histopathology. No significant increases in serum ALT and AST activities were observed in cyp2e1(-/-) mice when compared to wild-type counterparts after CCl4 exposure. No detectable abnormality in liver histology was found in cyp2e1(-/-) mice after CCl4 exposure. In contrast, CCl4 treatment resulted in 422- and 125-fold increases in serum ALT and AST activities, respectively, in wild-type mice. Consistent with the results of serum ALT and AST activities, severe hepatic damage was noted in livers of wild-type mice, indicating the importance of CYP2E1 in mediating the hepatic damage following CCl4 exposure in these mice. In addition, a dramatic decrease in CYP2E1-catalyzed p-nitrophenol activity and complete loss of immunoreactive CYP2E1 were observed in wild-type mice after CCl4 treatment, suggesting that CYP2E1 was degraded during the process of CCl4-induced hepatotoxicity, These studies conclusively demonstrate that CYP2E1 is the major factor involved in the CCl4-induced hepatotoxicity in mice. (C) 1998 Academic Press.
引用
收藏
页码:109 / 118
页数:10
相关论文
共 72 条
[1]  
AKAHORI A, 1983, JPN J EXP MED, V53, P199
[2]  
Albano E, 1987, Free Radic Res Commun, V3, P243, DOI 10.3109/10715768709069789
[3]   Methanol potentiation of carbon tetrachloride hepatotoxicity: The central role of cytochrome P450 [J].
Allis, JW ;
Brown, BL ;
Simmons, JE ;
Hatch, GE ;
McDonald, A ;
House, DE .
TOXICOLOGY, 1996, 112 (02) :131-140
[4]  
BRADFORD MM, 1976, ANAL BIOCHEM, V72, P248, DOI 10.1016/0003-2697(76)90527-3
[5]   EFFECTS OF DISULFIRAM ON HEPATIC P450IIE1, OTHER MICROSOMAL-ENZYMES, AND HEPATOTOXICITY IN RATS [J].
BRADY, JF ;
XIAO, F ;
WANG, MH ;
LI, Y ;
NING, SM ;
GAPAC, JM ;
YANG, CS .
TOXICOLOGY AND APPLIED PHARMACOLOGY, 1991, 108 (02) :366-373
[6]   ORAL TOXICITY OF CARBON-TETRACHLORIDE - ACUTE, SUBACUTE, AND SUBCHRONIC STUDIES IN RATS [J].
BRUCKNER, JV ;
MACKENZIE, WF ;
MURALIDHARA, S ;
LUTHRA, R ;
KYLE, GM ;
ACOSTA, D .
FUNDAMENTAL AND APPLIED TOXICOLOGY, 1986, 6 (01) :16-34
[7]  
BUHLER R, 1991, ALCOHOL ALCOHOLISM, P311
[8]  
CAMPBELL CB, 1980, NEW ZEAL MED J, V91, P381
[9]  
CHOPRA P, 1972, LAB INVEST, V26, P716
[10]  
CONNOR HD, 1990, MOL PHARMACOL, V37, P443