Effect of CYP2E1 gene deletion in mice on expression of microsomal epoxide hydrolase in response to VCD exposure

Aileen F. Keating, Kathila S. Rajapaksa, I. Glenn Sipes, Patricia B Hoyer

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

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 (129S1/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 (5μM) 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 μM, 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.

Original languageEnglish (US)
Pages (from-to)351-359
Number of pages9
JournalToxicological Sciences
Volume105
Issue number2
DOIs
StatePublished - 2008

Fingerprint

Epoxide Hydrolases
Cytochrome P-450 CYP2E1
Gene Deletion
Cytochrome P-450 Enzyme System
Protein Isoforms
Genes
Ovary
9,10-Dimethyl-1,2-benzanthracene
Metabolites
4-vinyl-1-cyclohexene dioxide
Detoxification
Ovarian Follicle
Epoxidation
Epoxy Compounds
Metabolism
Gene expression
Rodentia
Genotype
Gene Expression
Messenger RNA

Keywords

  • Cytochrome P450 isoform 2E1
  • Microsomal epoxide hydrolase
  • VCD-induced ovotoxicity

ASJC Scopus subject areas

  • Toxicology

Cite this

Effect of CYP2E1 gene deletion in mice on expression of microsomal epoxide hydrolase in response to VCD exposure. / Keating, Aileen F.; Rajapaksa, Kathila S.; Sipes, I. Glenn; Hoyer, Patricia B.

In: Toxicological Sciences, Vol. 105, No. 2, 2008, p. 351-359.

Research output: Contribution to journalArticle

Keating, Aileen F. ; Rajapaksa, Kathila S. ; Sipes, I. Glenn ; Hoyer, Patricia B. / Effect of CYP2E1 gene deletion in mice on expression of microsomal epoxide hydrolase in response to VCD exposure. In: Toxicological Sciences. 2008 ; Vol. 105, No. 2. pp. 351-359.
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