Abstract
The effects of three calcium antagonists, nifedipine (NF), verapamil (V) and diltiazem (DL), on rat liver monooxygenases were studied. The drugs were administered in oral doses of 50, 40 and 30 mg/kg daily for 3 weeks in male Wistar rats. NF and V shortened the hexobarbital (HB) sleeping time and increased benzphetamin-N-demethylase (BND), ethylmorphine-N-demethylase (EMND), aniline hydroxylase (AH), ethoxycoumarineO-deethylase (ECOD), ethoxyresorufin-O-deethylase (EROD) and NADPH-cytochrome c reductase activities and the content of cytochrome P-450 and microsomal heme, but did not change the content of cytochrome b5. The data suggest that these calcium antagonists exert an enzyme-inducing effect on the hepatic monooxygenases. DL significantly increased only the EROD and NADPH-cytochrome c reductase activities and shortened HB sleeping time to a lesser extent, suggesting a weaker enzymeinducing effect as compared to NF and V. The three drugs increased the δ-aminolevulinic acid (ALA) synthetase activity and decreased heme oxygenase (HO) activity. The increased cytochrome P-450 content is probably due to the increased synthesis and the decreased breakdown of this hemoprotein.
References
Aitio A (1978) A simple and sensitive assay of 7-ethoxycoumarine deethylation. Anal Biochem 85: 488–491
Burke MD, Mayer RT (1983) Differential effects of phenobarbitone and 3-methylcholanthrene induction of the hepatic microsomal metabolism and cytochrome P-450 binding of phenoxazone and a homologous series of its normal alkyl ethers (alkoxyresorufins). Chem Biol Interact 45: 243–258
Fleckenstein A, Fleckenstein-Grun G, Frey M, Thimm F (1990) Experimental antiarteriosclerotic effects of calcium antagonists. J Clin Pharmacol 30: 151–154
Glebov FP, Karpova MN (1990) The role of Ca2+ in the pathogenesis of epilepsy. Calcium antagonists — a new class of anticonvulsants. Patol Fisiol Eksp Ter 3: 57–61
Guengerich FP (1982) Microsomal enzymes involved in toxicology. Analysis and separation. In: Hayes AW (ed) Principles and methods of toxicology. Raven Press, New York, pp 609–634
Guengerich FP, Bocker R (1986) Mechanism of oxidation of dihydropyridines by cytochrome P-450. Fed Proc 45: 1871
Guengerich FP, Martin MV, Beaune PH, Kremers P, Wolff T, Waxman D (1986) Characterization of rat and human liver microsomal cytochrome P-450 forms involved in nifedipine oxidation, a prototype for genetic polymorphism in oxidative drug metabolism. J Biol Chem 261: 5051–5060
Guengerich FP, Brian WR, Iwasaki M, Sari M, Baarnhielm C, Bertsson P (1991) Oxidation of dihydropyridine calcium channel blockers and analogues by human liver cytochrome P-450IIIA4. J Med Chem 34: 1838–1844
Jones RM (1987) Calcium, its agonists and antagonists: past, present and future. J Soc Med 80: 136–137
Koleva MR, Stoytchev TS (1988) Effect of nifedipine on rat liver monooxygenases. Compt Rend Acad Bulg Sci 41: 147–149
Koleva MR, Stoytchev TS (1990) Liver monooxygenase activity after multiple application of nifedipine, verapamil and diltiazem. Acta Physiol Pharmacol Bulg 16: 16–21
Koleva MR, Stoytchev TS (1991) Effect of nifedipine, verapamil and diltiazem on drug metabolizing enzyme systems after single administration in rats. Compt Rend Acad Bulg Sci 44: 109–111
Koleva MR, Stoytchev TS, Gulyaeva L, Grishanova A, Mishin V, Lyakhovich V (1991) Induction of cytochrome P-450 isozymes upon repeated administration of nifedipine. Eur J Drug Metab Pharmacokinet 16: 103–106
Lydine P, Gillet G, Fabre I, Dalet-Beluche J, Bonfils C, Thenot J, Maurel P (1990) Identification of the rabbit and human cytochromes P-450IIIA as the major enzymes involved in the N-demethylation of diltiazem. Drug Metab Dispos 18: 711–719
Marver HS, Tschudy DT, Perloth M, Collins A (1966) Aminolevulinic acid synthetase. Studies in liver homogenates. J Biol Chem 241: 2803–2809
Mazel P (1972) Experiments illustrating drug metabolism in vitro. Determination of aniline hydroxylase. In: La Du BH, Mandel HG, Way EL (eds) Fundamentals of drug metabolism and drug disposition. Williams & Williams, Baltimore, pp 569–572
Nash T (1953) The colorimetric estimation of formaldehyde by means of the Hantzch reaction. J Biol Chem 55: 412–416
Nelson W, Olsen N (1988) Regiochemistry and enantioselectivity in the oxidative N-dealkylation of verapamil. Drug Metab Dispos 16: 834–841
Omura T, Sato R (1964) The carbon monooxide binding pigment of liver microsomes. I. Evidence for its hemoprotein nature. J Biol Chem 239: 2370–2378
Paul KG, Teorell H, Akeson A (1953) The molar light absorption of pyridine ferroprotoporphyrin (pyridine hemochromogen). Acta Chem Scand 7: 1284–1287
Renton K (1985) Inhibition of hepatic microsomal drug metabolism by the calcium channel blockers diltiazem and verapamil. Biochem Pharmacol 34: 2549–2553
Tenhunen R, Marver H, Schmid R (1968) The enzymatic conversion of heme to bilirubin by microsomal heme oxygenase. Proc Natl Acad Sci 61: 748–755
Vermilion J, Coon M (1978) Purified liver microsomal NADPH-cytochrome P-450 reductase. J Biol Chem 253: 2694–2704
Watkins PB, Maurel P, Schuets EG, Wrighton SA, Parker G, Guzelian PS (1985) Identification of human cytochrome P-450 isozymes inducible by glucocorticoids and macrolide antibiotics. Fed Proc 44: 1206–1210
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Koleva, M., Stoytchev, T. On the enzyme-inducing action of calcium antagonists. Arch Toxicol 67, 294–296 (1993). https://doi.org/10.1007/BF01974350
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DOI: https://doi.org/10.1007/BF01974350