Ovarian toxicity of 4-vinylcyclohexene and related olefins in B6C3F1 mice: role of diepoxides.
4-Vinylcyclohexene (VCH) is an ovarian toxicant in mice. Studies have established that bioactivation of VCH to epoxides is required for its ovotoxicity, with vinylcyclohexene diepoxide being the most potent epoxide of VCH in terms of follicular depletion. To determine the role of the diepoxide in the ovarian toxicity of VCH and related compounds, a structure-activity study was conducted. Following administration (ip) of VCH for 30 days, a significant depletion of ovarian follicles was observed. No alteration of small ovarian follicle counts occurred following treatment with structural analogues of VCH (vinylcyclohexane, ethylcyclohexene, and cyclohexene) that contain only a single unsaturated site. These VCH analogues were converted to monoepoxides both in vitro and in vivo. In addition, when the monoepoxide forms of the VCH analogues were administered to mice, they were not ovotoxic. These results indicate that vinylcyclohexene diepoxide may be the ultimate ovotoxic metabolite of VCH. A diepoxide was also shown to be critical for butadiene- and isoprene-induced follicular loss. Butadiene monoepoxide, butadiene diepoxide, and isoprene were ovotoxic. In contrast, the monoepoxide, epoxybutane, was not ovotoxic. The ovotoxicity of these compounds correlated with their chemical reactivity as assessed by alkylation of nicotinamide. Vinylcyclohexene diepoxide and butadiene diepoxide had a 3.5- to 10-fold higher chemical reactivity as compared to their monoepoxide precursors and structurally related monoepoxides. Thus, a relationship exists between chemical reactivity and ovotoxicity. Only those compounds which are metabolized to a diepoxide or are a diepoxide were ovotoxic. The formation of these diepoxide metabolites may in turn be linked to the ovarian toxicity and carcinogenicity of these olefins.
Doerr
J K
JK
Department of Pharmacology and Toxicology, University of Arizona, Tucson 85721, USA.
Hooser
S B
SB
Smith
B J
BJ
Sipes
I G
IG
D000475:Alkenes / Q000737:chemistry / Q000633:toxicity*; D000478:Alkylation; D000704:Analysis of Variance; D000818:Animals; D001711:Biotransformation; D002849:Chromatography, Gas; D003510:Cyclohexanes / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D053138:Cyclohexenes; D004852:Epoxy Compounds / Q000737:chemistry / Q000633:toxicity*; D005260:Female; D066298:In Vitro Techniques; D013058:Mass Spectrometry; D051379:Mice; D008815:Mice, Inbred Strains; D008862:Microsomes, Liver / Q000378:metabolism; D010053:Ovary / Q000187:drug effects*; D013329:Structure-Activity Relationship
D000475:Alkenes; D003510:Cyclohexanes; D053138:Cyclohexenes; D004852:Epoxy Compounds; C013733:4-vinylcyclohexene