Sex difference in induction of hepatic CYP2B and CYP3A subfamily enzymes by nicardipine and nifedipine in rats.
Male and female of F344 rats were treated per os with nicardipine (Nic) and nifedipine (Nif), and changes in the levels of mRNA and protein of hepatic cytochrome P450 (P450) enzymes, CYP2B1, CYP2B2, CYP3A1, CYP3A2, CYP3A9, and CYP3A18 were examined. Furthermore, hepatic microsomal activities for pentoxyresorufin O-dealkylation (PROD) and nifedipine oxidation, which are mainly mediated by CYP2B and CYP3A subfamily enzymes, respectively, were measured. Analyses of RT-PCR and Western blotting revealed that Nic and Nif induced predominantly CYP3A and CYP2B enzymes, respectively. As for the gene activation of CYP2B enzymes, especially CYP2B1, Nif showed high capacity in both sexes of rats, whereas Nic did a definite capacity in the males but little in the females. Gene activations of CYP3A1, CYP3A2, and CYP3A18 by Nic occurred in both sexes of rats, although that of CYP3A9 did only in the male rats. Although gene activations of CYP3A1 and CYP3A2 by Nif were observed in both sexes of rats, a slight activation of the CYP3A9 gene occurred only in female rats, and the CYP3A18 gene activation, in neither male nor female rats. Thus, changes in levels of the mRNA or protein of CYP2B and CYP3A enzymes, especially CYP2B1 and CYP3A2, were closely correlated with those in hepatic PROD and nifedipine oxidation activities, respectively. The present findings demonstrate for the first time the sex difference in the Nic- and Nif-mediated induction of hepatic P450 enzymes in rats and further indicate that Nic and Nif show different specificities and sex dependencies in the induction of hepatic P450 enzymes.
Konno
Yoshihiro
Y
Department of Molecular Toxicology and COE program in the 21st Century, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan.
Sekimoto
Masashi
M
Nemoto
Kiyomitsu
K
Degawa
Masakuni
M
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis*; D015153:Blotting, Western; D002121:Calcium Channel Blockers / Q000633:toxicity*; D019362:Cytochrome P-450 CYP2B1 / Q000096:biosynthesis; D051544:Cytochrome P-450 CYP3A; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D007527:Isoenzymes; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D009529:Nicardipine / Q000633:toxicity*; D009543:Nifedipine / Q000633:toxicity*; D010089:Oxidoreductases, N-Demethylating / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011916:Rats, Inbred F344; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012737:Sex Factors; D013250:Steroid Hydroxylases / Q000096:biosynthesis; D015533:Transcriptional Activation
D002121:Calcium Channel Blockers; D007527:Isoenzymes; D012333:RNA, Messenger; D009529:Nicardipine; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; D019362:Cytochrome P-450 CYP2B1; D051544:Cytochrome P-450 CYP3A; C025619:steroid 16-beta-hydroxylase; D010089:Oxidoreductases, N-Demethylating; D009543:Nifedipine