TY - JOUR
T1 - Influence of CYP2C19*18 and CYP2C19*19 alleles on omeprazole 5-hydroxylation
T2 - In vitro functional analysis of recombinant enzymes expressed in Saccharomyces cerevisiae
AU - Hanioka, Nobumitsu
AU - Tsuneto, Yumi
AU - Saito, Yoshiro
AU - Maekawa, Keiko
AU - Sawada, Jun Ichi
AU - Narimatsu, Shizuo
PY - 2008/4
Y1 - 2008/4
N2 - 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 Km value for omeprazole 5-hydroxylation of CYP2C19.1B was 1.46 μM. The Km value of CYP2C19.19 was significantly higher (1.5-fold) than that of CYP2C19.1B. Vmax and Vmax/Km 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 Vmax value of CYP2C19.19 was significantly higher (1.8-fold) than that of CYP2C19.1B, whereas the Vmax/Km value was comparable to that of CYP2C19.1B. In contrast, Km, V max and Vmax/Km 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.
AB - 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 Km value for omeprazole 5-hydroxylation of CYP2C19.1B was 1.46 μM. The Km value of CYP2C19.19 was significantly higher (1.5-fold) than that of CYP2C19.1B. Vmax and Vmax/Km 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 Vmax value of CYP2C19.19 was significantly higher (1.8-fold) than that of CYP2C19.1B, whereas the Vmax/Km value was comparable to that of CYP2C19.1B. In contrast, Km, V max and Vmax/Km 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.
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U2 - 10.1111/j.1742-7843.2008.00222.x
DO - 10.1111/j.1742-7843.2008.00222.x
M3 - Article
C2 - 18312490
AN - SCOPUS:40849102618
SN - 1742-7835
VL - 102
SP - 388
EP - 393
JO - Basic and Clinical Pharmacology and Toxicology
JF - Basic and Clinical Pharmacology and Toxicology
IS - 4
ER -