title: Cytochrome P450-dependent catabolism of vitamin K: ω-hydroxylation catalyzed by human CYP4F2 and CYP4F11.
abstract: Vitamin K plays an essential role in many biological processes including blood clotting, maintenance of bone health, and inhibition of arterial calcification. A menaquinone form of vitamin K, MK4, is increasingly recognized for its key roles in mitochondrial electron transport, as a ligand for the nuclear receptor SXR, which controls the expression of genes involved in transport and metabolism of endo- and xenobiotics, and as a pharmacotherapeutic in the treatment of osteoporosis. Although cytochrome P450 (CYP) 4F2 activity is recognized as an important determinant of phylloquinone (K1) metabolism, the enzymes involved in menaquinone catabolism have not been studied previously. CYP4F2 and CYP4F11 were expressed and purified and found to be equally efficient as in vitro catalysts of MK4 ω-hydroxylation. CYP4F2, but not CYP4F11, catalyzed sequential metabolism of MK4 to the ω-acid without apparent release of the intermediate aldehyde. The ω-alcohol could also be metabolized to the acid by microsomal NAD(+)-dependent alcohol and aldehyde dehydrogenases. LC-MS/MS analysis of trypsinized human liver microsomes (using a surrogate peptide approach) revealed the mean concentrations of CYP4F2 and CYP4F11 to be 14.3 and 8.4 pmol/mg protein, respectively. Microsomal MK4 ω-hydroxylation activities correlated with the CYP4F2 V433M genotype but not the CYP4F11 D446N genotype. Collectively, these data expand the lexicon of vitamin K ω-hydroxylases to include the 'orphan' P450 CYP4F11 and identify a common variant, CYP4F2 (rs2108622), as a major pharmacogenetic variable influencing MK4 catabolism.
authors.affiliation: Department of Medicinal Chemistry and ‡Department of Pharmaceutics, School of Pharmacy at the University of Washington , Box 357610, Seattle, Washington 98105, United States.
authors.forename: Katheryne Z
authors.initials: KZ
authors.lastname: Edson
authors.forename: Bhagwat
authors.initials: B
authors.lastname: Prasad
authors.forename: Jashvant D
authors.initials: JD
authors.lastname: Unadkat
authors.forename: Yoshitomo
authors.initials: Y
authors.lastname: Suhara
authors.forename: Toshio
authors.initials: T
authors.lastname: Okano
authors.forename: F Peter
authors.initials: FP
authors.lastname: Guengerich
authors.forename: Allan E
authors.initials: AE
authors.lastname: Rettie
mesh_terms: D042926:Cytochrome P-450 CYP4A / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D000072470:Cytochrome P450 Family 4; D006801:Humans; D006900:Hydroxylation; D007700:Kinetics; D008862:Microsomes, Liver / Q000201:enzymology; D024482:Vitamin K 2 / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D024482:Vitamin K 2; C030814:menatetrenone; D003577:Cytochrome P-450 Enzyme System; D000072470:Cytochrome P450 Family 4; C492722:CYP4F11 protein, human; C117480:CYP4F2 protein, human; D042926:Cytochrome P-450 CYP4A