Effect of ovariectomy and androgen on phenobarbital induction of hepatic CYP2B1 and CYP2B2 in Sprague-Dawley rats.
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 16beta-hydroxylase activity, benzyloxyresorufin O-dealkylase activity, pentoxyresorufin O-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 16beta-hydroxylase, benzyloxyresorufin O-dealkylase and pentoxyresorufin O-dealkylase) by phenobarbital. By comparison, postpubertal administration of testosterone enanthate (5 micromol/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 2alpha-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.
Chang
T K
TK
Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, Canada.
Anderson
M D
MD
Bandiera
S M
SM
Bellward
G D
GD
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D019362:Cytochrome P-450 CYP2B1 / Q000096:biosynthesis*; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004790:Enzyme Induction; D005260:Female; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D010052:Ovariectomy; D010053:Ovary / Q000502:physiology*; D010634:Phenobarbital / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013250:Steroid Hydroxylases / Q000096:biosynthesis*; D013739:Testosterone / Q000494:pharmacology*
D013739:Testosterone; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; D019362:Cytochrome P-450 CYP2B1; C025619:steroid 16-beta-hydroxylase; D010634:Phenobarbital