TY - JOUR
T1 - Functional characterization of 20 allelic variants of CYP1A2
AU - Ito, Miyabi
AU - Katono, Yuki
AU - Oda, Akifumi
AU - Hirasawa, Noriyasu
AU - Hiratsuka, Masahiro
N1 - Publisher Copyright:
© The Japanese Society for the Study of Xenobiotics. 2015 Published by Elsevier Ltd. All rights reserved.
PY - 2015/6/1
Y1 - 2015/6/1
N2 - Genetic variations in cytochrome P450 1A2 (CYP1A2) are associated with interindividual variability in the metabolism and efficacy of many medications. Twenty CYP1A2 variants harboring amino acid substitutions were analyzed for functional changes in enzymatic activity. Recombinant CYP1A2 variant proteins were heterologously expressed in COS-7 cells. Enzyme kinetic analyses were performed with two representative CYP1A2 substrates, phenacetin and 7-ethoxyresorufin. Among the 20 CYP1A2 allelic variants, CYP1A2∗4, CYP1A2∗6, CYP1A2∗8, CYP1A2∗15, CYP1A2∗16, and CYP1A2∗21 were inactive toward both substrates. CYP1A2∗11 showed markedly reduced activity, but the changes in Km were different between the substrates. CYP1A2∗14 and CYP1A2∗20 exhibited increased activity compared to the wild-type enzyme, CYP1A2∗1. This comprehensive in vitro assessment provided insight into the specific metabolic activities of CYP1A2 proteins encoded by variant alleles, which may to be valuable when interpreting the results of in vivo studies.
AB - Genetic variations in cytochrome P450 1A2 (CYP1A2) are associated with interindividual variability in the metabolism and efficacy of many medications. Twenty CYP1A2 variants harboring amino acid substitutions were analyzed for functional changes in enzymatic activity. Recombinant CYP1A2 variant proteins were heterologously expressed in COS-7 cells. Enzyme kinetic analyses were performed with two representative CYP1A2 substrates, phenacetin and 7-ethoxyresorufin. Among the 20 CYP1A2 allelic variants, CYP1A2∗4, CYP1A2∗6, CYP1A2∗8, CYP1A2∗15, CYP1A2∗16, and CYP1A2∗21 were inactive toward both substrates. CYP1A2∗11 showed markedly reduced activity, but the changes in Km were different between the substrates. CYP1A2∗14 and CYP1A2∗20 exhibited increased activity compared to the wild-type enzyme, CYP1A2∗1. This comprehensive in vitro assessment provided insight into the specific metabolic activities of CYP1A2 proteins encoded by variant alleles, which may to be valuable when interpreting the results of in vivo studies.
KW - 7-Ethoxyresorufin
KW - CYP1A2
KW - Cytochrome P450
KW - Genetic polymorphism
KW - Phenacetin
UR - http://www.scopus.com/inward/record.url?scp=84931569415&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84931569415&partnerID=8YFLogxK
U2 - 10.1016/j.dmpk.2015.03.001
DO - 10.1016/j.dmpk.2015.03.001
M3 - Article
C2 - 26022657
AN - SCOPUS:84931569415
SN - 1347-4367
VL - 30
SP - 247
EP - 252
JO - Drug Metabolism and Pharmacokinetics
JF - Drug Metabolism and Pharmacokinetics
IS - 3
ER -