Influence of CYP2C19*18 and CYP2C19*19 alleles on omeprazole 5-hydroxylation: In vitro functional analysis of recombinant enzymes expressed in Saccharomyces cerevisiae

Nobumitsu Hanioka, Yumi Tsuneto, Yoshiro Saito, Keiko Maekawa, Jun Ichi Sawada, Shizuo Narimatsu

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)388-393
Number of pages6
JournalBasic and Clinical Pharmacology and Toxicology
Volume102
Issue number4
DOIs
Publication statusPublished - Apr 2008

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Hydroxylation
Functional analysis
Omeprazole
Yeast
Saccharomyces cerevisiae
Alleles
Enzymes
Proton Pump Inhibitors
Gastric Acid
Metabolic Networks and Pathways
Metabolism
Cytochrome P-450 Enzyme System
Cytochrome P-450 CYP2C19
In Vitro Techniques
Yeasts
Cells
Acids
Substrates
Proteins

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology
  • Medicine(all)

Cite this

Influence of CYP2C19*18 and CYP2C19*19 alleles on omeprazole 5-hydroxylation : In vitro functional analysis of recombinant enzymes expressed in Saccharomyces cerevisiae. / Hanioka, Nobumitsu; Tsuneto, Yumi; Saito, Yoshiro; Maekawa, Keiko; Sawada, Jun Ichi; Narimatsu, Shizuo.

In: Basic and Clinical Pharmacology and Toxicology, Vol. 102, No. 4, 04.2008, p. 388-393.

Research output: Contribution to journalArticle

Hanioka, Nobumitsu ; Tsuneto, Yumi ; Saito, Yoshiro ; Maekawa, Keiko ; Sawada, Jun Ichi ; Narimatsu, Shizuo. / Influence of CYP2C19*18 and CYP2C19*19 alleles on omeprazole 5-hydroxylation : In vitro functional analysis of recombinant enzymes expressed in Saccharomyces cerevisiae. In: Basic and Clinical Pharmacology and Toxicology. 2008 ; Vol. 102, No. 4. pp. 388-393.
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abstract = "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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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

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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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