Drug Metabolism and Disposition 2001-11-01

Differential metabolism of 1,1-dichloroethylene in livers of A/J, CD-1, and C57BL/6 mice.

P G Forkert, S M Boyd

Index: Drug Metab. Dispos. 29(11) , 1396-402, (2001)

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Abstract

1,1-Dichloroethylene (DCE) causes hepatocellular necrosis that preferentially affects centrilobular hepatocytes. The cytotoxic lesion has been attributed to DCE oxidation mediated mainly by CYP2E1, resulting in formation of reactive intermediates including the DCE epoxide. Here, we have tested the hypothesis that differing levels of hepatic CYP2E1 in A/J, CD-1, and C57BL/6 (B6) mice lead to differences in magnitudes of DCE metabolism and severities of hepatotoxicity. Our results showed that amounts of the CYP2E1 protein were higher in A/J mice than in B6 and CD-1 mice. Covalent binding of DCE to liver proteins was variable in the three strains of mice and was higher in A/J than in B6 mice; intermediate levels were found in CD-1 mice. Levels of a DCE epoxide-derived glutathione conjugate detected in liver cytosol correlated with those present in bile extracts and were significantly higher in A/J than in CD-1 and B6 mice. Immunohistochemical studies showed that formation of DCE epoxide-cysteine protein adducts was enhanced in the livers of A/J mice, compared with those produced in the livers of CD-1 and B6 mice. Similarly, centrilobular necrosis was more severe in the livers of A/J mice than in those in either CD-1 or B6 mice. Levels of glutathione were similar in the three strains of untreated mice and were diminished at comparable levels in all mice. These results indicated that high expression of hepatic CYP2E1 in A/J mice coincided with increased DCE metabolism and enhanced severity of hepatotoxicity, relative to those in CD-1 and B6 mice.