Cytochrome P450-dependent catabolism of vitamin K: omega-hydroxylation catalyzed by human CYP4F2 and CYP4F11.
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Edson KZ, Prasad B, Unadkat JD, Suhara Y, Okano T, Guengerich FP, Rettie AE
Cytochrome P450-dependent catabolism of vitamin K: omega-hydroxylation catalyzed by human CYP4F2 and CYP4F11.
Biochemistry. 2013 Nov 19;52(46):8276-85. doi: 10.1021/bi401208m. Epub 2013 Nov 7.
- PubMed ID
- 24138531 [ View in PubMed]
- 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 omega-hydroxylation. CYP4F2, but not CYP4F11, catalyzed sequential metabolism of MK4 to the omega-acid without apparent release of the intermediate aldehyde. The omega-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 omega-hydroxylation activities correlated with the CYP4F2 V433M genotype but not the CYP4F11 D446N genotype. Collectively, these data expand the lexicon of vitamin K omega-hydroxylases to include the 'orphan' P450 CYP4F11 and identify a common variant, CYP4F2 (rs2108622), as a major pharmacogenetic variable influencing MK4 catabolism.
DrugBank Data that Cites this Article
- Drugs
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Phylloquinone Leukotriene-B(4) omega-hydroxylase 1 Protein Humans UnknownSubstrateDetails - Polypeptides
Name UniProt ID Phylloquinone omega-hydroxylase CYP4F2 P78329 Details - Drug Reactions
Reaction Details Details
