ToxSci Advance Access originally published online on July 12, 2008
Toxicological Sciences 2008 105(2):351-359; doi:10.1093/toxsci/kfn136
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Effect of CYP2E1 Gene Deletion in Mice on Expression of Microsomal Epoxide Hydrolase in Response to VCD Exposure
* Department of Physiology
Department of Pharmacology, University of Arizona, Tucson, Arizona 85724-5051
2 To whom correspondence should be addressed at Department of Physiology, University of Arizona, 1501 North Campbell Avenue, #4122, Tucson, AZ 85724-5051. Fax: (520) 626-2382. E-mail: hoyer{at}u.arizona.edu.
Received February 6, 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 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 (0.5–1µM, 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.
Key Words: VCD-induced ovotoxicity; cytochrome P450 isoform 2E1; microsomal epoxide hydrolase.
1 Present address: Amgen, Inc., Toxicology Department, Thousand Oaks, CA 91320-1799.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  M. Faut, C. Rodriguez de Castro, F. M Bietto, J. A Castro, and G. D Castro Metabolism of ethanol to acetaldehyde and increased susceptibility to oxidative stress could play a role in the ovarian tissue cell injury promoted by alcohol drinking Toxicology and Industrial Health, September 1, 2009; 25(8): 525 - 538. [Abstract] [PDF]
|
|