Functional characterization of 20 allelic variants of CYP1A2

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 prot...

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Veröffentlicht in:	Drug metabolism and pharmacokinetics 2015-06, Vol.30 (3), p.247-252
Hauptverfasser:	Ito, Miyabi, Katono, Yuki, Oda, Akifumi, Hirasawa, Noriyasu, Hiratsuka, Masahiro
Format:	Artikel
Sprache:	eng
Schlagworte:	7-Ethoxyresorufin Alleles Amino Acid Substitution Animals Blotting, Western Cercopithecus aethiops COS Cells CYP1A2 Cytochrome P-450 CYP1A2 - genetics Cytochrome P450 Genetic polymorphism Humans Oxazines - metabolism Phenacetin Phenacetin - metabolism Polymorphism, Genetic Substrate Specificity Transfection
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container_title	Drug metabolism and pharmacokinetics
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creator	Ito, Miyabi Katono, Yuki Oda, Akifumi Hirasawa, Noriyasu Hiratsuka, Masahiro
description	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, CYP1A24, CYP1A26, CYP1A28, CYP1A215, CYP1A216, and CYP1A221 were inactive toward both substrates. CYP1A211 showed markedly reduced activity, but the changes in Km were different between the substrates. CYP1A214 and CYP1A220 exhibited increased activity compared to the wild-type enzyme, CYP1A21. 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.
doi_str_mv	10.1016/j.dmpk.2015.03.001
format	Article
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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, CYP1A24, CYP1A26, CYP1A28, CYP1A215, CYP1A216, and CYP1A221 were inactive toward both substrates. CYP1A211 showed markedly reduced activity, but the changes in Km were different between the substrates. CYP1A214 and CYP1A220 exhibited increased activity compared to the wild-type enzyme, CYP1A21. 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.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>26022657</pmid><doi>10.1016/j.dmpk.2015.03.001</doi><tpages>6</tpages></addata></record>
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subjects	7-Ethoxyresorufin Alleles Amino Acid Substitution Animals Blotting, Western Cercopithecus aethiops COS Cells CYP1A2 Cytochrome P-450 CYP1A2 - genetics Cytochrome P450 Genetic polymorphism Humans Oxazines - metabolism Phenacetin Phenacetin - metabolism Polymorphism, Genetic Substrate Specificity Transfection
title	Functional characterization of 20 allelic variants of CYP1A2
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