INDUCTION OF HEPATIC CYTOCHROME P450 ISOFORMS BY NICARDIPINE AT THERAPEUTIC DOSES IN SPONTANEOUSLY HYPERTENSIVE RATS

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概要

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• 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 12.5mg/kg at 24-hr intervals for 14 days. Therapeutic effects on the development of hypertension were observed at doses of 5 and 12.5mg/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 12.5mg/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 (12.5mg/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.

• 日本トキシコロジー学会の論文
• 2007-02-16

著者

• DEGAWA Masakuni

  Department of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka

• Souma Shinji

  Department Of Molecular Toxicology And Coe Program In The 21st Century School Of Pharmaceutical Scie

• KASAHARA Toshihiko

  Department of Molecular Toxicology and COE Program in the 21st Century, School of Pharmaceutical Sci

• NEMOTO Kiyomitsu

  Department of Molecular Toxicology and COE Program in the 21st Century, School of Pharmaceutical Sci

• SEKIMOTO Masashi

  Department of Molecular Toxicology and COE Program in the 21st Century, School of Pharmaceutical Sci

• Miyajima S

  Department Of Environmental Health Faculty Of Pharmaceutical Sciences Hokuriku University

• Sato M

  Section Of Genetic Engineering Research Center For Genetic Engineering And Cell Transplantation Toka

• Kasahara Toshihiko

  Department Of Molecular Toxicology And Coe Program In The 21st Century School Of Pharmaceutical Scie

• Kasahara Toshihiko

  Department Of Applied Biochemistry Hiroshima University

• Sekimoto Masashi

  Department Of Molecular Toxicology And Global Coe Program School Of Pharmaceutical Sciences Universi

• Degawa M

  Department Of Molecular Toxicology And Global Coe Program School Of Pharmaceutical Sciences Universi

• Degawa Masakuni

  Department Of Hygienic Chemistry Faculty Of Pharmaceutical Sciences Tohoku University

• MIYAJIMA Shoji

  Department of Molecular Toxicology and COE Program in the 21st Century, School of Pharmaceutical Sci

• KINAE Yusuke

  Department of Molecular Toxicology and COE Program in the 21st Century, School of Pharmaceutical Sci

• Kinae Yusuke

  Department Of Molecular Toxicology And Coe Program In The 21st Century School Of Pharmaceutical Scie

• Nemoto Kiyomitsu

  Department Of Molecular Toxicology And Global Coe Program School Of Pharmaceutical Sciences Universi

• Degawa Masakuni

  Department Of Molecular Toxicology And Global Coe Program School Of Pharmaceutical Sciences Universi

• Degawa Masakuni

  Dep. Of Molecular Toxicology And Global Center Of Excellence Program School Of Pharmaceutical Scienc

• Miyajima Shoji

  Department of Molecular Toxicology and COE Program in the 21st Century, School of Pharmaceutical Sciences, University of Shizuoka

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