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ToxSci Advance Access originally published online on January 4, 2007
Toxicological Sciences 2007 96(2):327-334; doi:10.1093/toxsci/kfl202
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© The Author 2007. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Involvement of Microsomal Epoxide Hydrolase Enzyme in Ovotoxicity Caused by 7,12-Dimethylbenz[a]anthracene

Kathila S. Rajapaksa*, I. Glenn Sipes{dagger} and Patricia B. Hoyer*,1

* Department of Physiology, University of Arizona, Tucson, Arizona 85724-5051 {dagger} Department of Pharmacology, University of Arizona, Tucson, Arizona 85724-5050

1 To whom correspondence should be addressed at Department of Physiology, University of Arizona, 1501 N. Campbell Avenue, #4122, Tucson, AZ 85724-5051. Fax: (520) 626-2382. E-mail: hoyer{at}u.arizona.edu.

Received December 1, 2006; accepted December 27, 2006


  Abstract

Ovarian follicle disruption in mice caused by 7,12-dimethylbenz[a]anthracene (DMBA) is attributed to its bioactivation by CYP1B1 to a 3,4-epoxide which is then hydrolyzed to form a 3,4-diol by microsomal epoxide hydrolase (mEH). Further epoxidation by CYP1A1 or 1B1 forms the ultimate ovotoxicant, DMBA-3,4-diol-1,2-epoxide. Studies suggest that the mouse ovary expresses these enzymes, and thus, may be capable of bioactivating DMBA to its ovotoxic metabolite. The present study was designed to evaluate the role of ovarian mEH in DMBA-induced ovotoxicity using a novel neonatal mouse ovarian culture system. Ovaries from postnatal day (PND) 4 B6C3F1 mice were incubated with DMBA (12.5nM–1µM) for various lengths of time. Following incubation, ovaries were histologically evaluated or assessed for mEH protein or mRNA. Following 15 days of incubation, DMBA reduced (p < 0.05) healthy follicles at concentrations ≥ 12.5nM. At 1µM DMBA, follicle loss and increased mEH protein were measured (p < 0.05) by 6 h. mRNA encoding mEH markedly increased after 2 days of incubation, and this increase preceded accelerated follicle loss at 4 days. Furthermore, follicle loss induced by DMBA was prevented when cyclohexene oxide (2mM), an mEH inhibitor, was added to DMBA incubations. These studies suggest that the PND4 mouse ovary is capable of bioactivating DMBA to its ovotoxic form, and that ovarian mEH enzyme activity is likely involved. Furthermore, these observations support the use of a novel ovarian culture system to study ovary-specific metabolism of xenobiotic chemicals.

Key Words: DMBA; mEH; in vitro ovarian culture; ovary.


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A. F. Keating, K. S. Rajapaksa, I. G. Sipes, and P. B. Hoyer
Effect of CYP2E1 Gene Deletion in Mice on Expression of Microsomal Epoxide Hydrolase in Response to VCD Exposure
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[Abstract] [Full Text] [PDF]


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