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Different contributions of cytochrome P450 2C19 and 3A4 in the oxidation of omeprazole by human liver microsomes: effects of contents of these two forms in individual human samples.

Abstract

Omeprazole 5-hydroxylation and sulfoxidation activities were determined in liver microsomes of different humans whose levels of individual forms of cytochrome P450 (P450 or CYP) varied. Correlation coefficients between omeprazole 5-hydroxylation activities (when determined at a substrate concentration of 10 microM) and S-mephenytoin 4'-hydroxylation and testosterone 6beta-hydroxylation activities were found to be 0.64 and 0.67, respectively, in liver microsomes of 84 human samples examined. Omeprazole sulfoxidation activities in these human samples were correlated with testosterone 6beta-hydroxylation activities (r = 0. 86). Omeprazole 5-hydroxylation by liver microsomes of a human sample that contained relatively high levels of CYP3A4 and low levels of CYP2C19 were inhibited very significantly by ketoconazole and anti-CYP3A4 antibodies, although a human sample having high in CYP2C19 and low in CYP3A4 was found to be sensitive toward fluvoxamine and anti-CYP2C9 antibodies. Sulfaphenazole (at 100 microM) did not affect the omeprazole 5-hydroxylation and sulfoxidation catalyzed by human liver microsomes. Both recombinant human CYP2C19 and CYP3A4 enzymes had activities for omeprazole 5-hydroxylation, with low Km and high Vmax values for the former enzyme and high Km and low Vmax values for the CYP3A4. These results suggest that contributions of CYP2C19 and CYP3A4 in the omeprazole 5-hydroxylation depend upon the ratio of these two P450 levels in human liver microsomes. Omeprazole 5-hydroxylation activities of different human samples were found to be related to predicted values calculated from the kinetic parameters of recombinant enzymes and the levels of liver microsomal CYP2C19 and CYP3A4 enzymes. Finally, when recombinant human CYP2C19 and CYP3A4 were mixed at levels found in different human samples, relatively similar profiles of omeprazole oxidation by the recombinant and microsomal enzyme systems were determined by analysis of high-performance liquid chromatography. These results suggest that both CYP2C19 and CYP3A4 are involved in the 5-oxidation of omeprazole (at a substrate concentration of 10 microM) in human liver microsomes and that contributions of these P450 enzymes depend on the compositions of CYP2C19 and CYP3A4 in liver.

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  • Authors+Show Affiliations

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    Osaka Prefectural Institute of Public Health, 3-69 Nakamichi 1-chome, Higashinari-ku, Osaka 537, Japan.

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    Source

    MeSH

    Animals
    Anti-Ulcer Agents
    Aryl Hydrocarbon Hydroxylases
    Cytochrome P-450 CYP2C19
    Cytochrome P-450 CYP3A
    Cytochrome P-450 Enzyme System
    Fluvoxamine
    Humans
    Hydroxylation
    Ketoconazole
    Microsomes, Liver
    Mixed Function Oxygenases
    Omeprazole
    Rabbits
    Recombinant Proteins
    Sulfaphenazole

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't
    Research Support, U.S. Gov't, P.H.S.

    Language

    eng

    PubMed ID

    9353355

    Citation

    Yamazaki, H, et al. "Different Contributions of Cytochrome P450 2C19 and 3A4 in the Oxidation of Omeprazole By Human Liver Microsomes: Effects of Contents of These Two Forms in Individual Human Samples." The Journal of Pharmacology and Experimental Therapeutics, vol. 283, no. 2, 1997, pp. 434-42.
    Yamazaki H, Inoue K, Shaw PM, et al. Different contributions of cytochrome P450 2C19 and 3A4 in the oxidation of omeprazole by human liver microsomes: effects of contents of these two forms in individual human samples. J Pharmacol Exp Ther. 1997;283(2):434-42.
    Yamazaki, H., Inoue, K., Shaw, P. M., Checovich, W. J., Guengerich, F. P., & Shimada, T. (1997). Different contributions of cytochrome P450 2C19 and 3A4 in the oxidation of omeprazole by human liver microsomes: effects of contents of these two forms in individual human samples. The Journal of Pharmacology and Experimental Therapeutics, 283(2), pp. 434-42.
    Yamazaki H, et al. Different Contributions of Cytochrome P450 2C19 and 3A4 in the Oxidation of Omeprazole By Human Liver Microsomes: Effects of Contents of These Two Forms in Individual Human Samples. J Pharmacol Exp Ther. 1997;283(2):434-42. PubMed PMID: 9353355.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Different contributions of cytochrome P450 2C19 and 3A4 in the oxidation of omeprazole by human liver microsomes: effects of contents of these two forms in individual human samples. AU - Yamazaki,H, AU - Inoue,K, AU - Shaw,P M, AU - Checovich,W J, AU - Guengerich,F P, AU - Shimada,T, PY - 1997/11/14/pubmed PY - 1997/11/14/medline PY - 1997/11/14/entrez SP - 434 EP - 42 JF - The Journal of pharmacology and experimental therapeutics JO - J. Pharmacol. Exp. Ther. VL - 283 IS - 2 N2 - Omeprazole 5-hydroxylation and sulfoxidation activities were determined in liver microsomes of different humans whose levels of individual forms of cytochrome P450 (P450 or CYP) varied. Correlation coefficients between omeprazole 5-hydroxylation activities (when determined at a substrate concentration of 10 microM) and S-mephenytoin 4'-hydroxylation and testosterone 6beta-hydroxylation activities were found to be 0.64 and 0.67, respectively, in liver microsomes of 84 human samples examined. Omeprazole sulfoxidation activities in these human samples were correlated with testosterone 6beta-hydroxylation activities (r = 0. 86). Omeprazole 5-hydroxylation by liver microsomes of a human sample that contained relatively high levels of CYP3A4 and low levels of CYP2C19 were inhibited very significantly by ketoconazole and anti-CYP3A4 antibodies, although a human sample having high in CYP2C19 and low in CYP3A4 was found to be sensitive toward fluvoxamine and anti-CYP2C9 antibodies. Sulfaphenazole (at 100 microM) did not affect the omeprazole 5-hydroxylation and sulfoxidation catalyzed by human liver microsomes. Both recombinant human CYP2C19 and CYP3A4 enzymes had activities for omeprazole 5-hydroxylation, with low Km and high Vmax values for the former enzyme and high Km and low Vmax values for the CYP3A4. These results suggest that contributions of CYP2C19 and CYP3A4 in the omeprazole 5-hydroxylation depend upon the ratio of these two P450 levels in human liver microsomes. Omeprazole 5-hydroxylation activities of different human samples were found to be related to predicted values calculated from the kinetic parameters of recombinant enzymes and the levels of liver microsomal CYP2C19 and CYP3A4 enzymes. Finally, when recombinant human CYP2C19 and CYP3A4 were mixed at levels found in different human samples, relatively similar profiles of omeprazole oxidation by the recombinant and microsomal enzyme systems were determined by analysis of high-performance liquid chromatography. These results suggest that both CYP2C19 and CYP3A4 are involved in the 5-oxidation of omeprazole (at a substrate concentration of 10 microM) in human liver microsomes and that contributions of these P450 enzymes depend on the compositions of CYP2C19 and CYP3A4 in liver. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/9353355/Different_contributions_of_cytochrome_P450_2C19_and_3A4_in_the_oxidation_of_omeprazole_by_human_liver_microsomes:_effects_of_contents_of_these_two_forms_in_individual_human_samples_ L2 - http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=9353355 DB - PRIME DP - Unbound Medicine ER -