Abstract
4-Vinylcyclohexene (VCH), an ovarian toxicant in mice, is known to irreversibly deplete ovarian follicles as a consequence of VCH diepoxide formation. Because ovotoxicity requires repeated dosing of VCH, the effect of consecutive daily doses of VCH (7.5 mmol/kg/day) on mouse liver microsomal activities and VCH epoxidation was determined. Cytochromes P-450 2B and 2A (CYP2B and CYP2A), principle isoforms involved in the bioactivation of VCH, as well as CYP2E1 and CYP3A were evaluated. VCH exposure increased total cytochrome P-450 content (35–83% above control levels) after either 5, 10, or 15 days of treatment. Western blot analysis revealed an induction of CYP2A, CYP2B, and CYP2E1 at day 10. Elevated levels of CYP2A and CYP2B correlated with marker androstenedione and testosterone 16α- and 16β-hydroxylase activities. Microsomes prepared from mice pretreated with VCH for 10 days demonstrated an increase (≥2-fold) in the rate of VCH monoepoxide and diepoxide formation. Microsomal VCH epoxidation was increased to a similar extent by phenobarbital, acetone, and dexamethasone treatment. An increase in cytosolic glutathioneS-transferase activity was observed after repeated VCH treatment, an enzyme potentially involved in detoxification of the VCH epoxides. Interestingly, preliminary studies indicated that circulating levels of the monoepoxide (vinylcyclohexene 1,2-monoepoxide) and diepoxide of VCH were elevated after repeated dosing of VCH. Overall, the results indicate that repeated exposure of VCH in mice induces cytochrome P-450-dependent activities, and in turn induction of its metabolism. Additional studies examining the toxicokinetics of VCH after repeated exposure are required to further delineate the relevance of induction in VCH-induced ovotoxicity.
Footnotes
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Send reprint requests to: Dr. I. Glenn Sipes, Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, 1703 East Mabel, Tucson, AZ 85721.
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↵1 Present address: Molecular Biosystems, Inc., 10030 Barnes Canyon Road, San Diego, CA 92121-2789.
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↵2 Present address: Agouron Pharmaceuticals, Inc., 4245 Sorrento Valley Blvd, San Diego, CA 92121.
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↵3 Present address: AIT Laboratories, 5601 Fortune Circle South, Indianapolis, IN, 46241.
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This work was supported by the Center for Toxicology/Flinn Research Fellowship (J.K.D.S.), Chemical Manufacturers Association, NRSA Grant F32-ES05613 (J.C.K.), ES03619 (J.R.H) and National Institute of Environmental Health Sciences Grant ES06694-01. This study was presented in part at the 35th Annual Society of Toxicology Meeting, Anaheim, CA, March 1996.
- Abbreviations used are::
- VCH
- vinylcyclohexene
- VCD
- vinylcyclohexene diepoxide
- 1
- 2-VCHE, vinylcyclohexene 1,2-monoepoxide
- 7
- 8-VCHE, vinylcyclohexene 7,8-monoepoxide
- P-450
- cytochrome P-450
- PB
- phenobarbital
- DEX
- dexamethasone
- ACE
- acetone
- GST
- glutathione S-transferase
- GSH
- glutathione
- Received June 10, 1998.
- Accepted September 22, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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