Induction of hepatic cyp2b and cyp3a subfamily enzymes by nicardipine and nifedipine in mice.
1. Nicardipine (Nic) or nifedipine (Nif) was given to male and female C57BL/6J mice by a single gavage at doses of 100, 200 and 400 micromolkg(-1), and changes in the levels of mRNA and apoprotein of hepatic cytochrome P450 (P450) enzymes, including Cyp2b9, Cyp2b10, Cyp3a11 and Cyp3a41, were examined by reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blotting, respectively. 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. 2. Results from RT-PCR analysis revealed that Nic, but not Nif, showed a capacity for activating the Cyp3a11 gene in either sex of mice and that both chemicals could induce a male-selective activation of Cyp2b10 gene, although they had no capacity for activating the Cyp2b9 and Cyp3a41 genes in either sex. 3. Increased levels of the mRNAs of Cyp2b10 and Cyp3a11 were closely correlated with those of apoprotein and activity of the corresponding P450 subfamily enzymes. 4. The study demonstrated for the first time that Nic, but not Nif, showed the ability to induce Cyp3a11 in both sexes of mice, although both Nif and Nic led to a male-selective induction of Cyp2b10, and that Nic and Nif had no ability to induce Cyp2b9 and Cyp3a41 in either sex.
Konno
Y
Y
Department of Molecular Toxicology and COE Program in the 21st Century, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan.
Sekimoto
M
M
Nemoto
K
K
Degawa
M
M
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D000072467:Cytochrome P450 Family 2; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D009529:Nicardipine / Q000494:pharmacology*; D009543:Nifedipine / Q000494:pharmacology*; D010088:Oxidoreductases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D012737:Sex Factors; D013250:Steroid Hydroxylases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism
D002121:Calcium Channel Blockers; D008565:Membrane Proteins; D003577:Cytochrome P-450 Enzyme System; D009529:Nicardipine; C408695:Cyp3a41a protein, mouse; D010088:Oxidoreductases; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C101679:Cyp2b10 protein, mouse; C121503:Cyp2b9 protein, mouse; C496508:Cyp3a11 protein, mouse; D051544:Cytochrome P-450 CYP3A; D000072467:Cytochrome P450 Family 2; D010089:Oxidoreductases, N-Demethylating; D009543:Nifedipine