Drug Discov Ther. 2010;4(6):412-417.

Novel CYP2C19 629c>a mutant gene detection in Japanese subjects and estimation of its effect on conformation.

Kimura S, Hasegawa S, Kobayashi A, Yamaguchi H, Yohda M, Kubota T

Gene polymorphism is considered to be one of the causes of poor metabolism (PM), and approximately 20 mutants have been reported for CYP2C19 thus far. In our analysis of the CYP2C19*3 mutant gene, we detected new CYP2C19 SNPs by cross checking with different procedures. We confirmed a new c>a mutation at the 629 position. Among the 587 healthy Japanese volunteers studied, two subjects carrying a mutant CYP2C19 allele were found to be heterozygotes (0.17%). Accordingly, we predicted the effect of this novel mutation on CYP2C19 conformation. The 629c>a mutation was located on exon 4 and was an amino acid substitution, in which Thr210 was changed to Asn. The modeled structure of CYP2C19 showed that the hydrogen bond between the main chain oxygen of Ile207 and the side chain Oγ of Thr210 would be lost when Thr210 was substituted by Asn; however, no steric constraint was observed, although Asn is larger than Thr in size. Although the CYP2C19 629c>a mutation induces an amino acid substitution, it is predicted to scarcely change its conformation. On the basis of these findings, we speculate that the mutant is not a causative gene for PM in CYP2C19 carriers.

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