Disposition and metabolism of 4-vinyl-1-cyclohexene diepoxide in female Fischer 344 rats and B6C3F(1) mice

Abstract

4-Vinyl-1-cyclohexene diepoxide (VCD) is a known carcinogen, a direct acting mutagen, and an ovarian toxicant. Female B6C3F₁ mice are more susceptible to the ovarian toxicity of VCD than female Fischer 344 rats, a difference which may be explained by the disposition/metabolism of VCD. Following a single dose ¹⁴C-VCD was rapidly metabolized and excreted predominantly in the urine of both species. However, the excretion rate was higher in the female rats compared to female mice. The major metabolite present in rat urine was the 4-(1,2-dihydroxy) ethyl-1,2-dihydroxycyclohexane (tetrol). However, in the mouse, the tetrol was only a minor metabolite. The major metabolites appeared to be polar conjugates of VCD, which also appeared in rat urine. This difference in urinary metabolites indicates different metabolic pathways of VCD between the two species. The rat hydrolyzes VCD by epoxide hydrolase to form the tetrol and also conjugates VCD. The mouse conjugates VCD but has a reduced capacity to hydrolyze the epoxide moieties. To further characterize the disposition of VCD, blood kinetic parameters were investigated. Although both species rapidly cleared VCD from the plasma, the mouse had a shorter plasma t(1/2) and mean residence time (MRT). The volume of distribution was also five fold greater in the mouse compared to the rat. Therefore, VCD distributes from the plasma to tissues, possibly target tissues (ie. ovaries), more profoundly in the mouse than in the rat. In vitro metabolism studies were performed to determine if differences in epoxide hydrolase explain the inability of the mouse to excrete the tetrol metabolites. Although the K(m) was similar, the V(max) for conversion of VCD to the tetrol was four-fold higher in rat hepatic microsomes compared to those of the mouse. Therefore, differences in the disposition and metabolism of VCD exist between female Fischer 344 rats and B6C3F₁ mice. These differences explain, in part, the increased susceptibility of the mouse ovary to the toxic effects of VCD.