vitamin-k-1 and Metabolism--Inborn-Errors

The aim of this study was to reveal the contribution of CYP4F2, CYP2C9, and VKORC1 genetic polymorphisms on the pharmacokinetics and pharmacodynamics of warfarin in Japanese pediatric patients. Genetic analyses of CYP4F2 (rs2108622), CYP2C9 (*2 and *3), and VKORC1 (-1639G>A) were performed, and plasma unbound warfarin, vitamin K1 (VK1), and menaquinone-4 (MK-4) concentrations were determined in 37 Japanese pediatric patients. The patients with CYP4F2 variant alleles C/T and T/T scored significantly lower values for the warfarin sensitivity index (INR/Cpss) and had significantly higher plasma concentrations of MK-4 than patients with the CYP4F2 allele C/C. Moreover, the plasma MK-4 concentration was negatively correlated with the warfarin sensitivity index. In contrast, the VKORC1 genetic polymorphism did not influence the warfarin sensitivity index. In patients with the CYP2C9 *3 allele, the unbound oral clearance values (normalized to body surface area) for S-warfarin were found to be significantly lower than in patients with the wild-type allele. In conclusion, CYP4F2 genetic polymorphism and plasma MK-4 concentration influence the pharmacodynamics of warfarin, suggesting a mechanism though which CYP4F2 genotype affects warfarin dose.

Topics: Adolescent; Alleles; Anticoagulants; Aryl Hydrocarbon Hydroxylases; Asian People; Child; Child, Preschool; Cytochrome P-450 CYP2C9; Cytochrome P-450 Enzyme System; Cytochrome P450 Family 4; Drug Resistance; Female; Humans; Infant; Male; Metabolism, Inborn Errors; Polymorphism, Genetic; Vitamin K 1; Vitamin K 2; Vitamin K Epoxide Reductases; Warfarin

Warfarin is a rodenticide commonly used worldwide. It inhibits coagulation of blood by inhibiting vitamin K 2,3-epoxide reductase (VKOR) activity. An inadequate supply of vitamin K blocks the production of prothrombin and causes hemorrhage. Recently, warfarin-resistant brown rats (Rattus norvegicus) were found around the Aomori area of Japan. There is no significant difference in the metabolic activity of warfarin in sensitive and resistant brown rats. To clarify the mechanism underlying warfarin resistance, we cloned the VKORC1 gene from rats and identified a novel substitution of arginine to proline at position 33 of the VKORC1 amino acid sequence. Then, we determined the differences in kinetics of VKOR activity between warfarin-resistant and sensitive rats. Hepatic microsomal VKOR-dependent activity was measured over a range of vitamin K epoxide concentrations from 6.25 to 150 µM. The Vmax values of resistant rats (0.0029 ± 0.020 nmol/min/mg) were about one tenth of those of sensitive rats (0.29 ± 0.12 nmol/min/mg). The Km values of resistant rats (47 ± 32 µM) were similar to those of sensitive rats (59 ± 18 µM). Warfarin-sensitive rats exhibited enzyme efficiencies (Vmax/Km) which were ten-fold greater than those observed in resistant rats. It may mean that VKOR activity of warfarin-resistant Aomori rats is almost lost, because their enzymatic efficiencies are very low even without warfarin. Further studies are needed to clarify how these rats can survive with a markedly reduced VKOR activity and how they simultaneously exhibit warfarin resistance.

Topics: Animals; Female; Gene Expression Regulation, Enzymologic; Japan; Male; Metabolism, Inborn Errors; Mixed Function Oxygenases; Mutation; Rats; Rats, Sprague-Dawley; RNA, Messenger; Rodenticides; Vitamin K; Vitamin K 1; Vitamin K Epoxide Reductases; Warfarin