Functional characterization of 10 CYP4A11 allelic variants to evaluate the effect of genotype on arachidonic acid ω-hydroxylation

• Published in: Drug metabolism and pharmacokinetics Vol. 30; no. 1; pp. 119 - 122
• Main Authors: Saito, Takahiro, Honda, Masashi, Takahashi, Masamitsu, Tsukada, Chiharu, Ito, Miyabi, Katono, Yuki, Hosono, Hiroki, Saigusa, Daisuke, Suzuki, Naoto, Tomioka, Yoshihisa, Hirasawa, Noriyasu, Hiratsuka, Masahiro
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.02.2015
• Subjects: 20-HETE; Alleles; Animals; Arachidonic acid; Arachidonic Acid - metabolism; Cercopithecus aethiops; COS Cells; CYP4A11; Cytochrome P-450 CYP4A; Cytochrome P-450 Enzyme System - genetics; Cytochrome P-450 Enzyme System - metabolism; Cytochrome P450; Genetic polymorphisms; Genotype; Humans; Hydroxylation; Hypertension; Mutagenesis, Site-Directed; Polymorphism, Single Nucleotide; Transfection; Hypertension; 20-HETE; Arachidonic acid; Cytochrome P450; Genetic polymorphisms; CYP4A11
• ISSN: 1347-4367; 1880-0920; 1880-0920
• DOI: 10.1016/j.dmpk.2014.09.001

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.