title: Modulation of hepatic CYP2A1, CYP2C11, and CYP3A9 expression in adult rats by neonatal administration of tamoxifen.
abstract: To examine the effect of neonatal administration of tamoxifen on adult expression of hepatic cytochrome P-450 (CYP) enzymes and steroid 5alpha-reductase, male and female Sprague-Dawley rats were injected s.c. with tamoxifen (20 microg) or peanut oil (control) once daily at days 1 to 5 of age and sacrificed at 3 months of age. Neonatal tamoxifen treatment did not affect b.wt. or liver weight of adult male and female rats, but decreased testicular weight by approximately 40% in adult male rats. Neonatal administration of tamoxifen decreased hepatic microsomal testosterone 6beta- and 7alpha-hydroxylase activities in adult female rats whereas it did not alter steroid 5alpha-reductase activity. The same treatment increased testosterone 7alpha-hydroxylase activity, but did not affect testosterone 6beta-hydroxylase or steroid 5alpha-reductase activity in adult male rats. Immunoblot analysis indicated that neonatal tamoxifen treatment decreased CYP2C11 protein level by 26% and increased CYP2A1 protein content by 2.6-fold in adult male rats, whereas it had no effect on CYP3A or CYP2B protein expression. The reduction in the CYP3A-mediated testosterone 6beta-hydroxylase activity in adult female rats was accompanied by a decrease in CYP3A9 mRNA expression. Analysis of serum hormone levels indicated that neonatal exposure to tamoxifen resulted in a decrease in serum 17beta-estradiol concentration in adult female rats, whereas it did not alter serum testosterone concentration in adult male rats. In summary, treatment of neonatal rats with tamoxifen produced a long-lasting effect on hepatic CYP2A1, CYP2C11, and CYP3A9 expression in addition to testicular weight and serum 17beta-estradiol concentration.
authors.affiliation: Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Kawai
authors.forename: S M
authors.initials: SM
authors.lastname: Bandiera
authors.forename: T K
authors.initials: TK
authors.lastname: Chang
authors.forename: F M
authors.initials: FM
authors.lastname: Poulet
authors.forename: P M
authors.initials: PM
authors.lastname: Vancutsem
authors.forename: G D
authors.initials: GD
authors.lastname: Bellward
mesh_terms: D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000096:biosynthesis; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D001189:Aryl Hydrocarbon Hydroxylases; D001835:Body Weight / Q000187:drug effects; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis / Q000096:biosynthesis* / Q000378:metabolism; D000072467:Cytochrome P450 Family 2; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D015151:Immunoblotting; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D009929:Organ Size / Q000187:drug effects; D010089:Oxidoreductases, N-Demethylating / Q000032:analysis / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000032:analysis / Q000096:biosynthesis / Q000378:metabolism; D013256:Steroids / Q000097:blood; D013629:Tamoxifen / Q000494:pharmacology*; D013737:Testis / Q000187:drug effects / Q000502:physiology
chemical_list: D018931:Antineoplastic Agents, Hormonal; D013256:Steroids; D013629:Tamoxifen; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; D051544:Cytochrome P-450 CYP3A; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase; C034694:steroid 15-beta-hydroxylase; C022657:steroid hormone 6-beta-hydroxylase; C022724:testosterone 7-alpha-hydroxylase, hamster; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; D010089:Oxidoreductases, N-Demethylating