Effect of androgen administration during puberty on hepatic CYP2C11, CYP3A, and CYP2A1 expression in adult female rats.
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 2alpha-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 6beta- and 7alpha-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 micromol/kg/injection, respectively) during days 35-49 of age did not increase the mean CYP2C11 expression in 90-day-old female rats, although testosterone 2alpha-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.
Anderson
M D
MD
Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, B.C., Canada.
Bandiera
S M
SM
Chang
T K
TK
Bellward
G D
GD
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005260:Female; D006207:Half-Life; D007527:Isoenzymes / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013739:Testosterone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics
D007527:Isoenzymes; D013739:Testosterone; C004648:testosterone enanthate; D003577:Cytochrome P-450 Enzyme System