Abstract
The purpose of this study was to investigate the impact of prepubertal ovariectomy and postpubertal administration of testosterone on inducibility of rat hepatic CYP2B1 and CYP2B2 by phenobarbital. Intact adult male and female Sprague-Dawley rats were injected ip with sodium phenobarbital (10 mg/kg) or saline (control) once daily on days 129–135 of age and sacrificed one day after the last dose. Hepatic microsomal androstenedione 16β-hydroxylase activity, benzyloxyresorufin O-dealkylase activity, pentoxyresorufinO-dealkylase activity, and CYP2B1 protein levels were lower in phenobarbital-treated female rats than in phenobarbital-treated male rats. In contrast, there was no sex difference in inducibility of CYP2B2. The lesser inducibility of CYP2B1 in adult female rats was attributed to the presence of an intact ovary because prepubertal ovariectomy (day 25 of age) resulted in increased induction of CYP2B1 and its associated activities (androstenedione 16β-hydroxylase, benzyloxyresorufin O-dealkylase and pentoxyresorufinO-dealkylase) by phenobarbital. By comparison, postpubertal administration of testosterone enanthate (5 μmol/kg sc once daily on days 80–94 of age) did not enhance the inducibility of CYP2B1 or its associated activities in prepubertally ovariectomized adult (136-day-old) rats administered phenobarbital (10 mg/kg/day on days 129–135 of age). However, the androgen treatment did increase CYP2C11-dependent testosterone 2α-hydroxylase activity in the same microsomal samples. Overall, the results show a sex difference in phenobarbital induction of hepatic CYP2B1 but not CYP2B2 in adult Sprague-Dawley rats. They also indicate that prepubertal ovariectomy enhances the effect of phenobarbital on CYP2B1, whereas administration of testosterone enanthate postpubertally does not influence the inducibility of either CYP2B1 or CYP2B2 in prepubertally ovariectomized adult rats.
Footnotes
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Send reprint requests to: Dr. G. D. Bellward, Division of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, The University of British Columbia, 2146 East Mall, Vancouver, B.C., V6T 1Z3, Canada.
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This work was supported by the Medical Research Council of Canada. M.D.A. was supported by a postgraduate scholarship (PGS-A) from the Natural Sciences and Engineering Research Council of Canada. Part of this study was presented at the XIth International Symposium on Microsomes and Drug Oxidations, Los Angeles, CA, July, 1996.
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↵2 Individual cytochromes P450 are designated according to the systematic nomenclature (58).
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↵3 The term CYP2B is used when the cited study did not distinguish between the individual CYP2B enzymes.
- Abbreviations used are::
- CYP
- cytochrome P450
- GH
- growth hormone
- 4-MA
- 17β-N,N-diethylcarbamoyl-4-methyl-4-aza-5α-androstan-3-one
- SDS-PAGE
- sodium dodecyl sulfate-polyacrylamide gel electrophoresis
- Received December 20, 1996.
- Accepted April 8, 1997.
- The American Society for Pharmacology and Experimental Therapeutics