Induction of hepatic cytochrome P450 isoforms by nicardipine at therapeutic doses in spontaneously hypertensive rats.
Nicardipine hydrochloride (Nic), a calcium channel antagonist, is used for the treatment of hypertension. In the present study, we estimated its effects on the levels and activities of hepatic cytochrome P450 isoforms in spontaneously hypertensive rats given p.o. with Nic at a dose of 0.5, 2.5, 5, or 12.5 mg/kg at 24-hr intervals for 14 days. Therapeutic effects on the development of hypertension were observed at doses of 5 and 12.5 mg/kg/day. Significant increases in the levels of mRNAs and enzyme activities of hepatic P450 isoforms, CYP1A1 and/or CYP1A2, by 14-day repetitive treatment with Nic were observed at lower therapeutic doses, whereas the increase in protein levels for CYP1A2 was observed at a higher therapeutic dose of 12.5 mg/kg/day. Likewise, the activities of hepatic CYP2B and CYP3A subfamily enzymes were increased by the 14-day-treatment of Nic only at a therapeutic dose (12.5 mg/kg/day), whereas their mRNA and protein levels were increased at lower therapeutic doses. To date, the dihydropyridine family, including Nic, has been believed to have inhibitory effects on the activity of various cytochrome P450 enzymes, especially human CYP3A4. However, the present findings demonstrate for the first time that Nic-repetitive treatments at a therapeutic dose result in significant increases in the expressions and activities of hepatic CYP1A, CYP2B, and CYP3A subfamily enzymes. Therefore, the effects of dihydropyridine family on cytochrome P450 enzymes have to be further validated to provide information on its safe and beneficial therapeutic application.
Miyajima
Shoji
S
Department of Molecular Toxicology, COE Program in the 21st Century, School of Pharaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan.
Nemoto
Kiyomitsu
K
Sekimoto
Masashi
M
Kinae
Yusuke
Y
Kasahara
Toshihiko
T
Souma
Shinji
S
Degawa
Masakuni
M
D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases / Q000187:drug effects* / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction; D015870:Gene Expression / Q000187:drug effects*; D006973:Hypertension / Q000201:enzymology*; D008297:Male; D009529:Nicardipine / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR
D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D009529:Nicardipine; D001189:Aryl Hydrocarbon Hydroxylases