Abstract
This biochemical and pharmacokinetic investigation was undertaken to evaluate the effects of androgen administration during puberty on sex-dependent cytochrome P450 (CYP or P450) enzyme expression in adult female rats. Hepatic testosterone 2α-hydroxylase activity and CYP2C11 and CYP3A protein levels were elevated in prepubertally ovariectomized rats injected subcutaneously with testosterone enanthate at 35–49 days of age and killed 41 days after discontinuation of treatment. In contrast, testosterone 6β- and 7α-hydroxylase activities and CYP2A1 protein content were not affected. The increase in CYP2C11 and CYP3A was likely not due to circulating testosterone because plasma testosterone was undetectable. The calculated elimination half-life was 51 ± 6 hr (mean ± SE) after testosterone enanthate administration. By 80 days after treatment, CYP2C11 and CYP3A levels were no longer increased. To determine if CYP2C11 expression was responsive to a more periodic pattern of androgen release, ovariectomized rats were injected subcutaneously once or twice daily with unesterified testosterone (elimination half-life was 2.0 ± 0.3 hr, mean ± SE). Once- or twice-daily dosing (5 or 2.5 μmol/kg/injection, respectively) during days 35–49 of age did not increase the mean CYP2C11 expression in 90-day-old female rats, although testosterone 2α-hydroxylase activity and CYP2C11 protein content were elevated in three of the eight rats injected twice daily. Neither dosing regimen increased CYP3A or decreased CYP2A1 expression. In summary, the results indicate that treatment with testosterone enanthate during puberty resulted in a prolonged but reversible increase in hepatic expression of CYP2C11 and CYP3A.
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 funded by research grants from the Medical Research Council of Canada (to G.D.B. and S.M.B.). M.D.A. was supported by a postgraduate scholarship (PGS-A) from the Natural Sciences and Engineering Research Council of Canada. This study formed part of the M.Sc. thesis requirements at The University of British Columbia for M.D.A. Results were presented at the 37th Annual Meeting of the Society of Toxicology, Seattle, WA, March, 1998.
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↵2 Individual cytochromes P450 are designated according to the systematic nomenclature (Nelson et al.1996).
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↵3 Determination of CYP3A content in microsomes from female rats was not possible because CYP3A1 was the only purified CYP3A enzyme available for use as calibration standard for quantitation. Thus, CYP3A levels are expressed as the optical density (OD x mm) of the stained band relative to the optical density of an internal standard.
- Abbreviations used are::
- CYP or P450
- cytochrome P450
- GH
- growth hormone
- IgG
- immunoglobulin G
- LOQ
- limit of quantitation
- SDS-PAGE
- sodium dodecyl sulfate-polyacrylamide gel electrophoresis
- The American Society for Pharmacology and Experimental Therapeutics
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