title: Functional characterization of 10 CYP4A11 allelic variants to evaluate the effect of genotype on arachidonic acid ω-hydroxylation.
abstract: 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.
authors.affiliation: Laboratory of Pharmacotherapy of Life-Style Related Disease, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Saito
authors.affiliation: Laboratory of Pharmacotherapy of Life-Style Related Disease, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Honda
authors.affiliation: Laboratory of Pharmacotherapy of Life-Style Related Disease, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Takahashi
authors.affiliation: Laboratory of Pharmacotherapy of Life-Style Related Disease, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
authors.forename: Chiharu
authors.initials: C
authors.lastname: Tsukada
authors.affiliation: Laboratory of Pharmacotherapy of Life-Style Related Disease, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
authors.forename: Miyabi
authors.initials: M
authors.lastname: Ito
authors.affiliation: Laboratory of Pharmacotherapy of Life-Style Related Disease, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Katono
authors.affiliation: Laboratory of Pharmacotherapy of Life-Style Related Disease, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Hosono
authors.affiliation: Department of Integrative Genomics, Tohoku Medical Megabank, Tohoku University, Sendai, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Saigusa
authors.affiliation: Laboratory of Oncology, Pharmacy Practice and Sciences, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Suzuki
authors.affiliation: Laboratory of Oncology, Pharmacy Practice and Sciences, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Tomioka
authors.affiliation: Laboratory of Pharmacotherapy of Life-Style Related Disease, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
authors.forename: Noriyasu
authors.initials: N
authors.lastname: Hirasawa
authors.affiliation: Laboratory of Pharmacotherapy of Life-Style Related Disease, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan. Electronic address: mhira@m.tohoku.ac.jp.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Hiratsuka
mesh_terms: D000483:Alleles; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D019556:COS Cells; D002522:Chlorocebus aethiops; D042926:Cytochrome P-450 CYP4A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D005838:Genotype; D006801:Humans; D006900:Hydroxylation; D016297:Mutagenesis, Site-Directed; D020641:Polymorphism, Single Nucleotide; D014162:Transfection
chemical_list: D016718:Arachidonic Acid; D003577:Cytochrome P-450 Enzyme System; C465478:CYP4A11 protein, human; D042926:Cytochrome P-450 CYP4A
keywords: 20-HETE; Arachidonic acid; CYP4A11; Cytochrome P450; Genetic polymorphisms; Hypertension