RT Journal Article
SR Electronic
T1 Modulation of Hepatic CYP2A1, CYP2C11, and CYP3A9 Expression in Adult Rats by Neonatal Administration of Tamoxifen
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1392
OP 1398
VO 27
IS 12
A1 Masahiko Kawai
A1 Stelvio M. Bandiera
A1 Thomas K. H. Chang
A1 Frederique M. Poulet
A1 Paul M. Vancutsem
A1 Gail D. Bellward
YR 1999
UL http://dmd.aspetjournals.org/content/27/12/1392.abstract
AB To examine the effect of neonatal administration of tamoxifen on adult expression of hepatic cytochrome P-450 (CYP) enzymes and steroid 5α-reductase, male and female Sprague-Dawley rats were injected s.c. with tamoxifen (20 μg) 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 6β- and 7α-hydroxylase activities in adult female rats whereas it did not alter steroid 5α-reductase activity. The same treatment increased testosterone 7α-hydroxylase activity, but did not affect testosterone 6β-hydroxylase or steroid 5α-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 6β-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 17β-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 17β-estradiol concentration. The American Society for Pharmacology and Experimental Therapeutics