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ToxSci Advance Access published online on July 12, 2008
Toxicological Sciences, doi:10.1093/toxsci/kfn136
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© The Author 2008. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

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

Aileen F. Keating*, Kathila S. Rajapaksa*,{dagger}, I. Glenn Sipes{ddagger} and Patricia B. Hoyer*

* University of Arizona, Department of Physiology, Tucson, Arizona, 85724-5051, USA {dagger} Present address: Amgen Inc., Toxicology Department, Thousand Oaks, CA, 91320-1799, USA {ddagger} University of Arizona, Department of Pharmacology, Tucson, Arizona, 85724-5050, USA

akeating{at}email.arizona.edu

kathilar{at}amgen.com

sipes{at}email.arizona.edu

Corresponding author: Patricia B. Hoyer, PhD, University of Arizona, Department of Physiology, 1501 N. Campbell Ave., #4122, Tucson, Arizona 85724-5051. e-mail: hoyer{at}u.arizona.edu Fax number: (520)626-2382. Telephone number: (520)626-6688

Received February 6, 2008; revision received June 27, 2008; accepted July 7, 2008


  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 (VCM). VCD specifically destroys small pre-antral (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 (PND4) 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 timecourse (2-15 d), relative to control, VCD (5 µM) caused an increase (P < 0.05) in mEH mRNA by 0.5-fold (d 10) and 1.84-fold (d 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 d) 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.

Key Words: VCD-induced ovotoxicity; Cytochrome P450 isoform 2E1; Microsomal epoxide hydrolase.


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