Cytochrome P450 Family 4F2 and 4F11 Haplotype Mapping and Association with Hepatic Gene Expression and Vitamin K Hydroxylation Activity.

Autor: Alade AN; Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington 98195, United States., Claw KG; Department of Biomedical Informatics, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045-2559, United States., McDonald MG; Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle, Washington 98195, United States., Prasad B; College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, Washington 99210-1495, United States., Rettie AE; Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle, Washington 98195, United States., Thummel KE; Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington 98195, United States.
Jazyk: angličtina
Zdroj: ACS pharmacology & translational science [ACS Pharmacol Transl Sci] 2024 Feb 03; Vol. 7 (3), pp. 716-732. Date of Electronic Publication: 2024 Feb 03 (Print Publication: 2024).
DOI: 10.1021/acsptsci.3c00287
Abstrakt: This study evaluated the underlying mechanistic links between genetic variability in vitamin K metabolic pathway genes ( CYP4F2 and CYP4F11 ) and phylloquinone hydroxylation activity using genotype- and haplotype-based approaches. Specifically, we characterized genetic variability in the CYP4F2/CYP4F11 locus and compared common single allele genotypes and common haplotypes as predictors of hepatic gene expression, enzyme abundance, and phylloquinone (VK 1 ) ω-hydroxylation kinetics. We measured CYP4F2 and CYP4F11 mRNA levels, CYP4F2 and CYP4F11 protein abundances, and the VK 1 concentration-dependent ω-hydroxylation rate in matched human liver nucleic acid and microsome samples, utilizing a novel in vitro population modeling approach. Results indicate that accounting for the CYP4F2*3 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.
Competing Interests: The authors declare no competing financial interest.
(© 2024 American Chemical Society.)
Databáze: MEDLINE
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