Common variants of cytochrome P450 4F2 exhibit altered vitamin E-{omega}-hydroxylase specific activity.
Human cytochrome P450 4F2 (CYP4F2) catalyzes the ω-hydroxylation of the side chain of tocopherols (TOH) and tocotrienols (T3), the first step in their catabolism to polar metabolites excreted in urine. CYP4F2, in conjunction with α-TOH transfer protein, results in the conserved phenotype of selective retention of α-TOH. The purpose of this work was to determine the functional consequences of 2 common genetic variants in the human CYP4F2 gene on vitamin E-ω-hydroxylase specific activity using the 6 major dietary TOH and T3 as substrate. CYP4F2-mediated ω-hydroxylase specific activity was measured in microsomal preparations from insect cells that express wild-type or polymorphic variants of the human CYP4F2 protein. The W12G variant exhibited a greater enzyme specific activity (pmol product · min(-1) · pmol CYP4F2(-1)) compared with wild-type enzyme for both TOH and T3, 230-275% of wild-type toward α, γ, and δ-TOH and 350% of wild-type toward α, γ, and δ-T3. In contrast, the V433M variant had lower enzyme specific activity toward TOH (42-66% of wild type) but was without a significant effect on the metabolism of T3. Because CYP4F2 is the only enzyme currently shown to metabolize vitamin E in humans, the observed substrate-dependent alterations in enzyme activity associated with these genetic variants may result in alterations in vitamin E status in individuals carrying these mutations and constitute a source of variability in vitamin E status.
Bardowell
Sabrina A
SA
Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA.
Stec
David E
DE
Parker
Robert S
RS
D016718:Arachidonic Acid / Q000737:chemistry / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism*; D000072470:Cytochrome P450 Family 4; D008401:Gas Chromatography-Mass Spectrometry; D056726:Genetic Association Studies; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000737:chemistry / Q000378:metabolism; D006900:Hydroxylation; D007700:Kinetics; D020641:Polymorphism, Single Nucleotide; D011994:Recombinant Proteins / Q000378:metabolism; D013379:Substrate Specificity; D024505:Tocopherols / Q000737:chemistry / Q000378:metabolism; D024508:Tocotrienols / Q000737:chemistry / Q000378:metabolism; D014810:Vitamin E / Q000737:chemistry / Q000378:metabolism*; D024502:alpha-Tocopherol
D006893:Hydroxyeicosatetraenoic Acids; D011994:Recombinant Proteins; D024508:Tocotrienols; D014810:Vitamin E; D016718:Arachidonic Acid; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D003577:Cytochrome P-450 Enzyme System; D000072470:Cytochrome P450 Family 4; C117480:CYP4F2 protein, human; D024502:alpha-Tocopherol; D024505:Tocopherols