Functional characterization of two novel CYP2C19 variants (CYP2C1918 and CYP2C1919) found in a Japanese population

• Published in: Xenobiotica 2007-04, Vol.37 (4), p.342-355
• Main Authors: Hanioka, N., Tsuneto, Y., Saito, Y., Sumada, T., Maekawa, K., Saito, K., Sawada, J., Narimatsu, S.
• Format: Article
• Language: English
• Subjects: Amino Acid Substitution; Aryl Hydrocarbon Hydroxylases - biosynthesis; Aryl Hydrocarbon Hydroxylases - chemistry; Aryl Hydrocarbon Hydroxylases - genetics; Asian Continental Ancestry Group; CYP2C19; CYP2C1918; CYP2C1919; Cytochrome P-450 CYP2C19; genetic polymorphism; Humans; Japan; Kinetics; Mephenytoin - chemistry; Mixed Function Oxygenases - biosynthesis; Mixed Function Oxygenases - chemistry; Mixed Function Oxygenases - genetics; Mutation, Missense; Recombinant Proteins - biosynthesis; Recombinant Proteins - chemistry; Recombinant Proteins - genetics; S-mephenytoin 4′-hydroxylation; Saccharomyces cerevisiae - genetics; Substrate Specificity - genetics
• ISSN: 0049-8254; 1366-5928
• DOI: 10.1080/00498250601127038

Cytochrome P450 2C19 (CYP2C19) plays an important role in the metabolism of a wide range of therapeutic drugs and exhibits genetic polymorphism with interindividual differences in metabolic activity. We have previously described two CYP2C19 allelic variants, namely CYP2C19*18 and CYP2C19*19 with Arg329His/Ile331Val and Ser51Gly/Ile331Val substitutions, respectively. In order to investigate precisely the effect of amino acid substitutions on CYP2C19 function, CYP2C19 proteins of the wild-type (CYP2C19.1B having Ile331Val) and variants (CYP2C19.18 and CYP2C19.19) were heterologously expressed in yeast cells, and their S-mephenytoin 4′-hydroxylation activities were determined. The Km value of CYP2C19.19 for S-mephenytoin 4′-hydroxylation was significantly higher (3.0-fold) than that of CYP2C19.1B. Although no significant differences in Vmax values on the basis of microsomal and functional CYP protein levels were observed between CYP2C19.1B and CYP2C19.19, the Vmax/Km values of CYP2C19.19 were significantly reduced to 29-47% of CYP2C19.1B. By contrast, the Km, Vmax or Vmax/Km values of CYP2C19.18 were similar to those of CYP2C19.1B. These results suggest that Ser51Gly substitution in CYP2C19.19 decreases the affinity toward S-mephenytoin of CYP2C19 enzyme, and imply that the genetic polymorphism of CYP2C19*19 also causes variations in the clinical response to drugs metabolized by CYP2C19.