Epoxidation of 4-vinylcyclohexene by human hepatic microsomes

Carcinogenicity studies have shown that chronic administration of 4-vinylcyclohexene (VCH) will induce ovarian tumors in B6C3F1 mice but not F-344 rats. This occurs because the blood level of the ovotoxic VCH metabolite, VCH-1,2-epoxide, is dramatically higher in VCH-treated female mice compared with rats. This species difference in VCH epoxidation is also reflected in the rate of VCH metabolism by hepatic microsomes (female mouse greater than female rat). The present study assessed the ability of microsomes obtained from human liver to metabolize VCH to epoxides since humans are exposed to VCH in certain occupational settings. The production of VCH-1,2-epoxide and VCH-7,8-epoxide from VCH (1 mM) by human hepatic microsomes was linear with respect to microsomal protein concentration (0.25-1.0 mg/ml) and incubation time (5-20 min). VCH-1,2-epoxide was the major metabolite, while the rate VCH-7,8-epoxide formation was about 6-fold lower and in some cases was below the limit of detection. There was no dramatic difference in the rate of VCH epoxidation by hepatic microsomes obtained from male and female humans. The rate of VCH-1,2-epoxide formation by female human hepatic microsomes was 0.71 +/- 0.35 nmol/mg microsomal protein/min (n = 4). This is 13- and 2-fold lower than the rate of VCH-1,2-epoxide formation by female mouse and rat hepatic microsomes, respectively. Therefore, if the rate of hepatic VCH epoxidation is the main factor which determines the ovotoxicity of VCH, then the results of these studies suggest that rats are the more appropriate animal model for extrapolation of animal data to humans.