Effects of Metronidazole, Azanidazole, and Azathioprine on Cytochrome P450 and Various Mono-Oxygenase Activities in Hepatic Microsomes from Control and Induced Mice

  • G. Cantelli-Forti
  • M. Paolini
  • P. Hrelia
  • E. Sapigni
  • G. L. Biagi
Part of the Archives of Toxicology, Supplement book series (TOXICOLOGY, volume 11)

Abstract

Drugs containing the imidazole ring have been reported to exert a potent inhibi­tory effect on microsomal mixed function mono-oxygenase (MFO) activity in man and experimental animals (Wilkinson et al. 1972; Pelkonen and Puurunen 1980; Murray 1984; Kapetanovic and Kupferberg 1984; Koop and Coon 1984; Kadderis and Rickert 1985; Horai et al. 1985). Such effects, mainly found in the liver and, recently, also in gonad and adrenal tissues (Mason et al. 1985), depend upon many factors. Species- and age-related differences have been established (Tu et al. 1981; Hajek and Novak 1982; Reinke et al. 1985). However, single or repeated administration of some imidazole derivatives was shown to result in an inhibition or an induction of MFO activity (Hajek and Novak 1982). By consider­ing the multiplicity of cytochrome (Cyt) P450 isoenzymes in microsomes, these conflicting results become understandable.

Keywords

Morphan Carbamazepine Cimetidine Metronidazole Quinoline 

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References

  1. Biagi GL, Barbaro AM, Guerra MC, Cantelli-Forti G, Aicardi G, Borea PA (1983) Quantitative relationship between structure and mutagenic activity in a series of 5-nitroimidazoles. Teratogen Carcin Mut 3:429–438CrossRefGoogle Scholar
  2. Cantelli-Forti G, Aicardi G, Guerra MC, Barbaro AM, Biagi GL (1983) Mutagenicity of a series of 25 nitroimidazoles and two nitrothiazoles in Salmonella typhimurium. Teratogen Care Mut 3:51–63CrossRefGoogle Scholar
  3. Cantelli-Forti G, Paolini M, Hrelia P, Corsi C, Biagi GL, Bronzetti G (1984) NADPH-generating system: influences on microsomal mono-oxygenase stability during incubations for the liver microsomal assay with rat and mouse S9 fractions. Mutat Res 129:291–297CrossRefGoogle Scholar
  4. Cantelli-Forti G, Hrelia P, Paolini M, Bronzetti G, Biagi GL (1985) The organo-specific activity of metronidazole and azanidazole in the intrasanguinous host-mediated assay. Drug Exp Clin Res 11:755–759Google Scholar
  5. Gervasi PG, Benedetti D, Citti L, Del Monte M, Turchi G (1984) Dinemorphan N-demethylation by mouse liver microsomes. Experientia 40:180–182PubMedCrossRefGoogle Scholar
  6. Hajek KK, Novak RF (1982) Spectral and metabolic properties of liver microsomes from imidazole-pretreated rabbit. Biochem Biophys Res Commun 108:664–672PubMedCrossRefGoogle Scholar
  7. Horai Y, White PF, Trevor AY (1985) The effect of etomidate on rabbit liver microsomal drug metabolism in vitro. Drug Metab Dispos 13:364–367PubMedGoogle Scholar
  8. Kapetanovic IM, Kupferberg HJ (1984) Nafimidone and imidazole anticonvulsant and its metabolite as potent inhibitors of microsomal metabolism of phenytoin and carbamazepine. Drug Metab Dispos 12:560–563PubMedGoogle Scholar
  9. Kadderis GL, Rickert DE (1985) Loss of rat liver microsomal cytochrome P-450 during methimazole and metabolism. Drug Metab Dispos 13:58–61Google Scholar
  10. Klotz AV, Stageman VV, Walsh C (1984) An alternative 7-ethoxycoumarin O-deethylase activity assay: a continuous visible spectrophotometric method for measurement of cytochrome P-450 mono-oxygenase activity. Anal Biochem 140:138–145PubMedCrossRefGoogle Scholar
  11. Koop DR, Coon MJ (1984) Purification of liver microsomal cytochrome P-450 isoenzymes 3a and 6 from imidazole treated rabbits. Mol Pharmacol 25:494–501PubMedGoogle Scholar
  12. Mason JI, Murray BA, Olcott M, Sheets JJ (1985) Imidazole antimycotics: inhibitors of steroid aromatase. Biochem Pharmacol 34:1087–1092PubMedCrossRefGoogle Scholar
  13. Murray M (1984) In vitro effects of quinoline derivatives on cytochrome P-450 and aminopyrine N-demethylase activity in rat hepatic microsomes. Biochem Pharmacol 33:3277–3281PubMedCrossRefGoogle Scholar
  14. Omura T, Sato R (1964) The carbon monoxide-binding pigment of liver microsomes. I. Evidence for its hemoprotein nature. J Biol Chem 239:2370–2378PubMedGoogle Scholar
  15. Pelkonen O, Puurunen J (1980) The effect of cimetidine on in vitro and in vivo microsomal drug metabolism in the rat. Biochem Pharmacol 29:3075–3080PubMedCrossRefGoogle Scholar
  16. Reinke LA, Sexter SH, Rikans LE (1985) Comparison of ethanol and imidazole pretreatments on hepatic mono-oxygenase activities in the rat. Res Commun Chem Pathol Pharmacol 47:97–105PubMedGoogle Scholar
  17. Tu YY, Sonnenberg J, Lewis KF, Yang CS (1981) Pyrazole-induced cytochrome P-450 in rat liver microsomes: an isozyme with high affinity for dimethylnitrosamine. Biochem Biophys Res Commun 103:905–912PubMedCrossRefGoogle Scholar
  18. Warkman P (1980) Pharmacokinetics of hypoxic cell radiosensitizers. Cancer Clin Trials 3:237–241Google Scholar
  19. Wilkinson CF, Hetnarski CF, Yellin TO (1972) Imidazole-derivatives. A new class of microsomal enzyme inhibitors. 21:3187–3192Google Scholar

Copyright information

© Springer-Verlag 1987

Authors and Affiliations

  • G. Cantelli-Forti
    • 1
  • M. Paolini
    • 1
  • P. Hrelia
    • 1
  • E. Sapigni
    • 1
  • G. L. Biagi
    • 1
  1. 1.Istituto di Farmacologia dell’UniversitáBolognaItaly

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