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Influence of CYP2C19*18 and CYP2C19*19 Alleles on Omeprazole 5‐Hydroxylation: In vitro Functional Analysis of Recombinant Enzymes Expressed in Saccharomyces cerevisiae
Author(s) -
Hanioka Nobumitsu,
Tsuneto Yumi,
Saito Yoshiro,
Maekawa Keiko,
Sawada Junichi,
Narimatsu Shizuo
Publication year - 2008
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/j.1742-7843.2008.00222.x
Subject(s) - cyp2c19 , omeprazole , hydroxylation , chemistry , enzyme , biochemistry , cytochrome p450 , cyp3a4 , metabolism , biology , stereochemistry , pharmacology
Omeprazole is one of the most widely used proton pump inhibitors for the treatment of gastric acid‐related disorders. The major metabolic pathway of omeprazole is 5‐hydroxylation, which is catalysed by CYP2C19. In this study, the effect of CYP2C19*18 and CYP2C19*19 alleles on omeprazole 5‐hydroxylation was studied using recombinant CYP2C19 enzymes of wild‐type (CYP2C19.1B having Ile331Val) and variants (CYP2C19.18 having Arg329His/Ile331Val and CYP2C19.19 Ser51Gly/Ile331Val) expressed in yeast cells. The K m value for omeprazole 5‐hydroxylation of CYP2C19.1B was 1.46 µM. The K m value of CYP2C19.19 was significantly higher (1.5‐fold) than that of CYP2C19.1B. V max and V max / K m values for omeprazole 5‐hydroxylation of CYP2C19.1B on the basis of cytochrome P450 protein level were 8.09 pmol/min./pmol CYP and 5.45 µl/min./pmol CYP, respectively. The V max value of CYP2C19.19 was significantly higher (1.8‐fold) than that of CYP2C19.1B, whereas the V max / K m value was comparable to that of CYP2C19.1B. In contrast, K m , V max and V max / K m values of CYP2C19.18 were similar to those of CYP2C19.1B. These results suggest that CYP2C19*19 allele decreases the affinity between CYP2C19 enzyme and the substrate in omeprazole metabolism.