Changes in hepatic cytochrome P450 enzymes by cis- and trans-1,2-dichloroethylenes in rat

Abstract

1. We examined the effect of cis- and trans-1,2-dichloroethylen es (DCEs) on hepatic microsomalcytochrome P450 (P450) enzymes in the male and female rat. Rats were treated intraperitoneal ly with 7 5 mmol kg cis- or trans-1,2-DCE daily for 4 days. 2. Among the hepatic microsomal P450-dependent monooxygenase activities tested, testosterone 2α-hydroxylase (T2AH) activity in the male rat, which is associated with CYP2C11, was decreased by both cis- and trans-1,2-DCE isomers. The levels to control activities were 53 and 63 % respectively. Furthermore, immunoblottingshowed that both isomers significantly reduced the CYP2C11 6 protein level in liver microsomes from the male. The levels of testosterone 6β-hydroxylase (T6BH) activity and CYP3A2 1 protein in the male rat were reduced by cis-1,2-DCE but not trans-1,2-DCE. 3. cis-1,2-DCE decreased ethoxycoumarin O-deethylase (ECOD), benzyloxyresorufin O-debenzylase (BROD), chlorzoxazone 6-hydroxylase (CZ6H) and testosterone 7α-hydroxylase (T7AH) activities in the male rat by 29, 28, 34 and 27 % respectively. On the other hand, trans-1,2-DCE significantly increased 7-ethoxyresorufin O-deethylase (EROD) and 7-methoxyresorufin O-demethylase (MROD) activities in the male rat 1.4- and 1.9-fold respectively. Immunoblottingshowed that cis-1,2-DCE reduced CYP1A1 2 and CYP2B1/2 protein levels, whereas trans-1,2-DCE increased CYP1A1/2 and CYP2B1/2 protein levels in the male rat. 4. The activities of other P450-dependent monooxygenases, namely benzphetamine N-demethylase (BZND), aminopyrine N-demethylase (APND), erythromycin N-demethylase (EMND) and lauric acid ω-hydroxylase (LAOH), in the male rat were hardly affected by either 1,2-DCE isomer. In the female rat there were no apparent changes in P450-dependent monooxygenase activities upon treatment with the 1,2-DCE isomers. 5. These results suggest that 1,2-DCEs mainly affect male-specific P450 isoforms in the rat liver and that these changes may relate to the toxicity of 1,2-DCEs.