TY - JOUR
T1 - Functional characterization of 10 CYP4A11 allelic variants to evaluate the effect of genotype on arachidonic acid ω-hydroxylation
AU - Saito, Takahiro
AU - Honda, Masashi
AU - Takahashi, Masamitsu
AU - Tsukada, Chiharu
AU - Ito, Miyabi
AU - Katono, Yuki
AU - Hosono, Hiroki
AU - Saigusa, Daisuke
AU - Suzuki, Naoto
AU - Tomioka, Yoshihisa
AU - Hirasawa, Noriyasu
AU - Hiratsuka, Masahiro
N1 - Funding Information:
This study was supported in part by a grant from the Ministry of Health, Labour and Welfare, Japan (‘Initiative to facilitate development of innovative drug, medical devices, and cellular & tissue-based product’), Smoking Research Foundation , and Japan Research Foundation for Clinical Pharmacology . We thank the Biomedical Research Core of Tohoku University Graduate School of Medicine for technical support.
Publisher Copyright:
© 2014 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.
PY - 2015/2
Y1 - 2015/2
N2 - Genetic variations in cytochrome P450 4A11 (CYP4A11) contributes to inter-individual variability in the metabolism of fatty acids such as arachidonic acid. CYP4A11 metabolizes arachidonic acid to 20-hydroxyeicosatetraenoic acid (20-HETE), which is important for the regulation of blood pressure. Polymorphisms in CYP4A11 are associated with susceptibility to hypertension. In this study, we evaluated the in vitro ω-hydroxylation of arachidonic acid by 10 CYP4A11 allelic variants, which cause amino acid substitutions in the encoded proteins. CYP4A11 variants were heterologously expressed in COS-7 cells and the kinetic parameters of arachidonic acid ω-hydroxylation were estimated. Among 10 CYP4A11 variants, 5 (CYP4A11-v1, CYP4A11-v2, CYP4A11-v3, CYP4A11-v4, and CYP4A11-v7) showed no or markedly lower activity compared to wild-type CYP4A11. This functional analysis of CYP4A11 variants could provide useful information for the effective prevention and treatment of hypertension.
AB - Genetic variations in cytochrome P450 4A11 (CYP4A11) contributes to inter-individual variability in the metabolism of fatty acids such as arachidonic acid. CYP4A11 metabolizes arachidonic acid to 20-hydroxyeicosatetraenoic acid (20-HETE), which is important for the regulation of blood pressure. Polymorphisms in CYP4A11 are associated with susceptibility to hypertension. In this study, we evaluated the in vitro ω-hydroxylation of arachidonic acid by 10 CYP4A11 allelic variants, which cause amino acid substitutions in the encoded proteins. CYP4A11 variants were heterologously expressed in COS-7 cells and the kinetic parameters of arachidonic acid ω-hydroxylation were estimated. Among 10 CYP4A11 variants, 5 (CYP4A11-v1, CYP4A11-v2, CYP4A11-v3, CYP4A11-v4, and CYP4A11-v7) showed no or markedly lower activity compared to wild-type CYP4A11. This functional analysis of CYP4A11 variants could provide useful information for the effective prevention and treatment of hypertension.
KW - 20-HETE
KW - Arachidonic acid
KW - CYP4A11
KW - Cytochrome P450
KW - Genetic polymorphisms
KW - Hypertension
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U2 - 10.1016/j.dmpk.2014.09.001
DO - 10.1016/j.dmpk.2014.09.001
M3 - Article
C2 - 25760539
AN - SCOPUS:84924995854
VL - 30
SP - 119
EP - 122
JO - Drug Metabolism and Pharmacokinetics
JF - Drug Metabolism and Pharmacokinetics
SN - 1347-4367
IS - 1
ER -