Effect of CYP2E1 gene deletion in mice on expression of microsomal epoxide hydrolase in response to VCD exposure.
Females are born with a finite number of primordial follicles. 4-Vinylcyclohexene diepoxide (VCD) is a metabolite formed by epoxidation of 4-vinylcyclohexene (VCH) via its two monoepoxides 1,2- and 7,8-4-vinylcyclohexene monoepoxide (VCM). VCD specifically destroys small preantral (primordial and small primary) follicles in the rodent ovary. The phase I enzyme, cytochrome P450 isoform 2E1 (CYP2E1) is involved in ovarian metabolism of VCM to VCD. Further, microsomal epoxide hydrolase (mEH) can detoxify VCD to an inactive tetrol (4-(1,2-dihydroxy)ethyl-1,2-dihydroxycyclohexane). This study evaluated the effects of VCD-induced ovotoxicity on mEH in CYP2E1+/+ and -/- mice (129S(1)/SvImJ background strain) using a postnatal day 4 mouse whole ovary culture system. The hypothesis of our study is that there is a relationship between CYP2E1 and mEH gene expression in the mouse ovary. Relative to control, VCD exposure caused follicle loss (p < 0.05) in ovaries from both genotypes; however, after 15 days, this loss was greater (p < 0.05) in CYP2E1+/+ ovaries. In a time course (2-15 days), relative to control, VCD (5 microM) caused an increase (p < 0.05) in mEH mRNA by 0.5-fold (day 10) and 1.84-fold (day 15) in CYP2E1-/- but not +/+ ovaries. 7,12-Dimethylbenz[a]anthracene (DMBA) also destroys ovarian follicles but, unlike VCD, is bioactivated by mEH to an ovotoxic 3,4-diol-1,2-epoxide metabolite. Incubation of ovaries in increasing concentrations of DMBA (0.5-1 microM, 15 days) resulted in greater (p < 0.05) follicle loss in CYP2E1-/-, relative to +/+ ovaries. With greater mEH (CYP2E1-/-), increased follicle loss with DMBA (bioactivation) and decreased follicle loss with VCD (detoxification) support that ovarian expression of CYP2E1 and mEH may be linked.
Keating
Aileen F
AF
Department of Physiology, University of Arizona, Tucson, Arizona 85724-5051, USA.
Rajapaksa
Kathila S
KS
Sipes
I Glenn
IG
Hoyer
Patricia B
PB
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D000831:Animals, Newborn; D053138:Cyclohexenes / Q000378:metabolism / Q000633:toxicity*; D019392:Cytochrome P-450 CYP2E1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004851:Epoxide Hydrolases / Q000235:genetics / Q000378:metabolism*; D005260:Female; D017353:Gene Deletion; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D009924:Organ Culture Techniques; D006080:Ovarian Follicle / Q000187:drug effects / Q000201:enzymology; D010053:Ovary / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D014753:Vinyl Compounds / Q000378:metabolism / Q000633:toxicity*
D053138:Cyclohexenes; D012333:RNA, Messenger; D014753:Vinyl Compounds; D015127:9,10-Dimethyl-1,2-benzanthracene; C012606:4-vinyl-1-cyclohexene dioxide; D019392:Cytochrome P-450 CYP2E1; D004851:Epoxide Hydrolases