Functional Characterization of 29 Cytochrome P450 4F2 Variants Identified in a Population of 8380 Japanese Subjects and Assessment of Arachidonic Acid ω -Hydroxylation
Drug Metabolism and Disposition, ISSN: 0090-9556, Vol: 51, Issue: 12, Page: 1561-1568
2023
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Article Description
Cytochrome P450 4F2 (CYP4F2) is an enzyme that is involved in the metabolism of arachidonic acid (AA), vitamin E and K, and xenobiotics including drugs. CYP4F2*3 polymorphism (rs2108622; c.1297G>A; p.Val433Met) has been associated with hypertension, ischemic stroke, and variation in the effectiveness of the anticoagulant drug warfarin. In this study, we characterized wild-type CYP4F2 and 28 CYP4F2 variants, including a Val433Met substitution, detected in 8380 Japanese subjects. The CYP4F2 variants were heterologously expressed in 293FT cells to measure the concentrations of CYP4F2 variant holoenzymes using carbon monoxide–reduced difference spectroscopy, where the wild type and 18 holoenzyme variants showed a peak at 450 nm. Kinetic parameters [ Vmax, substrate concentration producing half of Vmax ( S50 ), and intrinsic clearance (CL int ) as Vmax / S50 ] of AA ω -hydroxylation were determined for the wild type and 21 variants with enzyme activity. Compared with the wild type, two variants showed significantly decreased CL int values for AA ω -hydroxylation. The values for seven variants could not be determined because no enzymatic activity was detected at the highest substrate concentration used. Three-dimensional structural modeling was performed to determine the reason for reduced enzymatic activity of the CYP4F2 variants. Our findings contribute to a better understanding of CYP4F2 variant-associated diseases and possible future therapeutic strategies. CYP4F2 is involved in the metabolism of arachidonic acid and vitamin K, and CYP4F2*3 polymorphisms have been associated with hypertension and variation in the effectiveness of the anticoagulant drug warfarin. This study presents a functional analysis of 28 CYP4F2 variants identified in Japanese subjects, demonstrating that seven gene polymorphisms cause loss of CYP4F2 function, and proposes structural changes that lead to altered function.
Bibliographic Details
http://www.sciencedirect.com/science/article/pii/S0090955624010924; http://dx.doi.org/10.1124/dmd.123.001389; http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85173683591&origin=inward; http://www.ncbi.nlm.nih.gov/pubmed/37775333; https://linkinghub.elsevier.com/retrieve/pii/S0090955624010924; https://dx.doi.org/10.1124/dmd.123.001389; https://dmd.aspetjournals.org/content/51/12/1561
Elsevier BV
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