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.

[1]  R. Morrison,et al.  Quantitative PCR assay for cytochromes P450 2B and 3A induction in rat precision-cut liver slices: correlation study with induction in vivo. , 2005, Journal of pharmacological and toxicological methods.

[2]  Koujirou Yamamoto,et al.  Inhibitory effects of nicardipine to cytochrome P450 (CYP) in human liver microsomes. , 2005, Biological & pharmaceutical bulletin.

[3]  B. Carter Antihypertensive drug interactions. , 2005, Drugs of today.

[4]  K. Nemoto,et al.  Induction of hepatic Cyp2b and Cyp3a subfamily enzymes by nicardipine and nifedipine in mice , 2004, Xenobiotica; the fate of foreign compounds in biological systems.

[5]  M. Degawa,et al.  Gene activations of CYP2B1 and CYP3A1 by dihydropyridine calcium channel antagonists in the rat liver: the structure-activity relationship. , 2004, Biological & pharmaceutical bulletin.

[6]  K. Nemoto,et al.  Sex difference in induction of hepatic CYP2B and CYP3A subfamily enzymes by nicardipine and nifedipine in rats. , 2004, Toxicology and applied pharmacology.

[7]  S. Fukuda,et al.  Age-related changes in blood pressure, hematological values, concentrations of serum biochemical constituents and weights of organs in the SHR/Izm, SHRSP/Izm and WKY/Izm. , 2004, Experimental animals.

[8]  K. Nemoto,et al.  Induction of hepatic cytochrome P450s responsible for the metabolism of xenobiotics by nicardipine and other calcium channel antagonists in the male rat , 2003, Xenobiotica; the fate of foreign compounds in biological systems.

[9]  J. Pascussi,et al.  Calcium channel modulators of the dihydropyridine family are human pregnane X receptor activators and inducers of CYP3A, CYP2B, and CYP2C in human hepatocytes. , 2001, Drug metabolism and disposition: the biological fate of chemicals.

[10]  H. Yamazaki,et al.  Inhibition of human cytochrome P450 enzymes by 1,4-dihydropyridine calcium antagonists: prediction of in vivo drug–drug interactions , 2000, European Journal of Clinical Pharmacology.

[11]  B. Ma,et al.  Drug interactions with calcium channel blockers: possible involvement of metabolite-intermediate complexation with CYP3A. , 2000, Drug metabolism and disposition: the biological fate of chemicals.

[12]  R. Edwards,et al.  Effect of calcium channel antagonists nifedipine and nicardipine on rat cytochrome P-450 2B and 3A forms. , 1999, The Journal of pharmacology and experimental therapeutics.

[13]  M. Gómez-Lechón,et al.  Long‐term expression of differentiated functions in hepatocytes cultured in three‐dimensional collagen matrix , 1998, Journal of cellular physiology.

[14]  D. Sonnichsen,et al.  Clinically Significant Cytochrome P‐450 Drug Interactions—A Comment , 1998, Pharmacotherapy.

[15]  Elizabeth Landrum Michalets,et al.  Update: Clinically Significant Cytochrome P‐450 Drug Interactions , 1998, Pharmacotherapy.

[16]  D. Waxman,et al.  Enhanced cyclophosphamide and ifosfamide activation in primary human hepatocyte cultures: response to cytochrome P-450 inducers and autoinduction by oxazaphosphorines. , 1997, Cancer research.

[17]  K. Lindros,et al.  Hormonal regulation of the zonated expression of cytochrome P-450 3A in rat liver. , 1995, The Biochemical journal.

[18]  R. Weaver,et al.  Cytochrome P450 specificities of alkoxyresorufin O-dealkylation in human and rat liver. , 1994, Biochemical pharmacology.

[19]  P. Thomas,et al.  Methoxyresorufin and benzyloxyresorufin: substrates preferentially metabolized by cytochromes P4501A2 and 2B, respectively, in the rat and mouse. , 1993, Biochemical pharmacology.

[20]  Z. Y. Chen,et al.  Differential regulation of cytochrome(s) P450 2B1/2 by phenobarbital in hepatic hyperplastic nodules induced by aflatoxin B1 or diethylnitrosamine plus 2-acetylaminofluorene in male F344 rats. , 1991, Toxicology and applied pharmacology.

[21]  R. Novak,et al.  Pyridine effects on expression and molecular regulation of the cytochrome P450IA gene subfamily. , 1991, Molecular pharmacology.

[22]  F. Guengerich Reactions and significance of cytochrome P-450 enzymes. , 1991, The Journal of biological chemistry.

[23]  C. Omiecinski,et al.  Developmental expression and in situ localization of the phenobarbital-inducible rat hepatic mRNAs for cytochromes CYP2B1, CYP2B2, CYP2C6, and CYP3A1. , 1990, Molecular pharmacology.

[24]  P. Maurel,et al.  Cyclosporin A drug interactions. Screening for inducers and inhibitors of cytochrome P-450 (cyclosporin A oxidase) in primary cultures of human hepatocytes and in liver microsomes. , 1990, Drug metabolism and disposition: the biological fate of chemicals.

[25]  I. Wool,et al.  The primary structure of rat ribosomal proteins: the amino acid sequences of L27a and L28 and corrections in the sequences of S4 and S12. , 1990, Biochimica et biophysica acta.

[26]  V. Timofeev,et al.  Conformational dynamic properties of water-soluble coupling factor of photophosphorylation studied by spin-labelling , 1990 .

[27]  T. Agatsuma,et al.  Hepatocarcinogenic heterocyclic aromatic amines that induce cytochrome P-448 isozymes, mainly cytochrome P-448H (P-450IA2), responsible for mutagenic activation of the carcinogens in rat liver. , 1989, Carcinogenesis.

[28]  O. Pelkonen,et al.  Inhibition of hepatic microsomal drug metabolism in rats by five calcium antagonists. , 1989, Pharmacology & toxicology.

[29]  M. Juchau,et al.  On the substrate specificity of cytochrome P450IIIA1. , 1988, Molecular pharmacology.

[30]  R. Meehan,et al.  Regulation of phenobarbital-inducible cytochrome P-450s in rat and mouse liver following dexamethasone administration and hypophysectomy. , 1988, The Biochemical journal.

[31]  D. Waxman,et al.  Characterization of rat and human liver microsomal cytochrome P-450 forms involved in nifedipine oxidation, a prototype for genetic polymorphism in oxidative drug metabolism. , 1986, The Journal of biological chemistry.

[32]  S. Higuchi,et al.  Comparative pharmacokinetics of nicardipine hydrochloride, a new vasodilator, in various species. , 1980, Xenobiotica; the fate of foreign compounds in biological systems.

[33]  S. Higuchi,et al.  Pharmacokinetic studies on nicardipine hydrochloride, a new vasodilator, after repeated administration to rats, dogs and humans. , 1980, Xenobiotica; the fate of foreign compounds in biological systems.

[34]  S. Higuchi,et al.  Metabolic fate of nicardipine hydrochloride, a new vasodilator, by various species in vitro. , 1980, Xenobiotica; the fate of foreign compounds in biological systems.

[35]  Charles W. Dunnett,et al.  New tables for multiple comparisons with a control. , 1964 .

[36]  K. Okamoto,et al.  Development of a strain of spontaneously hypertensive rats. , 1963, Japanese circulation journal.

[37]  O. H. Lowry,et al.  Protein measurement with the Folin phenol reagent. , 1951, The Journal of biological chemistry.