TY - JOUR
T1 - Functional characterization of two novel CYP2C19 variants (CYP2C19*18 and CYP2C19*19) found in a Japanese population
AU - Hanioka, N.
AU - Tsuneto, Y.
AU - Saito, Y.
AU - Sumada, T.
AU - Maekawa, K.
AU - Saito, K.
AU - Sawada, J.
AU - Narimatsu, S.
N1 - Funding Information:
We thank Dr Joyce A. Goldstein, National Institute of Environmental Health Sciences (Research Triangle Park, NC, USA) for providing CYP2C19*1A cDNA cloned into pBluescript-SK(±) vector. This work was supported in part by Health and Labor Sciences Research Grants from the Ministry of Health and Labor and Welfare, and in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan.
PY - 2007/4
Y1 - 2007/4
N2 - 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.
AB - 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.
KW - CYP2C19
KW - CYP2C1918
KW - CYP2C1919
KW - Genetic polymorphism
KW - S-mephenytoin 4'-hydroxylation
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U2 - 10.1080/00498250601127038
DO - 10.1080/00498250601127038
M3 - Article
C2 - 17455109
AN - SCOPUS:34147150215
VL - 37
SP - 342
EP - 355
JO - Xenobiotica
JF - Xenobiotica
SN - 0049-8254
IS - 4
ER -