biostudies-literatureAlade ANNational Center for Research ResourcesNCRR NIH HHSNational Institute of General Medical SciencesNIGMS NIH HHS716-732https://www.ebi.ac.uk/biostudies/studies/S-EPMC10928895biostudies-literatureUnknown7(3)This study evaluated the underlying mechanistic links between genetic variability in vitamin K metabolic pathway genes (<i>CYP4F2</i> and <i>CYP4F11</i>) and phylloquinone hydroxylation activity using genotype- and haplotype-based approaches. Specifically, we characterized genetic variability in the <i>CYP4F2/CYP4F11</i> locus and compared common single allele genotypes and common haplotypes as predictors of hepatic gene expression, enzyme abundance, and phylloquinone (VK₁) ω-hydroxylation kinetics. We measured <i>CYP4F2</i> and <i>CYP4F11</i> mRNA levels, CYP4F2 and CYP4F11 protein abundances, and the VK₁ concentration-dependent ω-hydroxylation rate in matched human liver nucleic acid and microsome samples, utilizing a novel <i>in vitro</i> population modeling approach. Results indicate that accounting for the <i>CYP4F2*3</i> allele alone is sufficient to capture most of the genetic-derived variability in the observed phenotypes. Additionally, our findings highlight the important contribution that CYP4F11 makes toward vitamin K metabolism in the human liver.ACS pharmacology & translational scienceCytochrome P450 Family <i>4F2</i> and <i>4F11</i> Haplotype Mapping and Association with Hepatic Gene Expression and Vitamin K Hydroxylation Activity.PMC10928895TL1-RR025016P01 GM116691TL1 RR025016P01-GM116691Alade ANPrasad BClaw KGRettie AEThummel KEMcDonald MGfalseCytochrome P450 Family <i>4F2</i> and <i>4F11</i> Haplotype Mapping and Association with Hepatic Gene Expression and Vitamin K Hydroxylation Activity.This study evaluated the underlying mechanistic links between genetic variability in vitamin K metabolic pathway genes (<i>CYP4F2</i> and <i>CYP4F11</i>) and phylloquinone hydroxylation activity using genotype- and haplotype-based approaches. Specifically, we characterized genetic variability in the <i>CYP4F2/CYP4F11</i> locus and compared common single allele genotypes and common haplotypes as predictors of hepatic gene expression, enzyme abundance, and phylloquinone (VK₁) ω-hydroxylation kinetics. We measured <i>CYP4F2</i> and <i>CYP4F11</i> mRNA levels, CYP4F2 and CYP4F11 protein abundances, and the VK₁ concentration-dependent ω-hydroxylation rate in matched human liver nucleic acid and microsome samples, utilizing a novel <i>in vitro</i> population modeling approach. Results indicate that accounting for the <i>CYP4F2*3</i> allele alone is sufficient to capture most of the genetic-derived variability in the observed phenotypes. Additionally, our findings highlight the important contribution that CYP4F11 makes toward vitamin K metabolism in the human liver.2024-01-01T00:00:00Z2024 Mar2026-06-02T10:10:35.41Z2025-04-03T23:26:37.154ZS-EPMC109288953848168310.1021/acsptsci.3c00287