Inhibition by warfarin of liver microsomal vitamin K-reductase in warfarin-resistant and susceptible rats

Biochemical Pharmacology
A D MacNicollM G Townsend

Abstract

The NADH-dependent vitamin K-reductase activity of liver microsomes from three closely related rat strains has been studied. One strain (TAS) is susceptible and two strains (HW and HS) resistant to the anticoagulant and lethal effects of warfarin. The effects of cofactors, temperature, detergent and dithiothreitol on vitamin K1 reduction and solvent extraction of substrate and product have been investigated. Vitamin K-reductase activity was inhibited by approximately 13 and 8% respectively when microsomal preparations from TAS and HW animals were incubated with 50 microM vitamin K1 and 10 microM warfarin. In HS rat liver microsomes the enzyme was highly resistant to inhibition by warfarin. Evidence is presented and discussed that suggests that NADH-dependent vitamin K-reductase may be inhibited in the anticoagulant effect of warfarin and may be altered as a result of expression of the warfarin-resistance gene in HS rats. The enzyme activity studied was probably not a DT-diaphorase although both NADH and NADPH acted as cofactors for the reaction.

References

Dec 1, 1973·FEBS Letters·C LindA D Martin
Aug 19, 1967·Nature·J H Greavses, P Ayres
Jan 15, 1982·Biochemical and Biophysical Research Communications·M J Fasco, L M Principe
Dec 31, 1980·Biochemical and Biophysical Research Communications·M J Fasco, L M Principe

Citations

Jan 1, 1987·Reviews on Drug Metabolism and Drug Interactions·F A SutcliffeG G Gibson
Mar 1, 1987·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·J W Suttie
Jan 20, 2006·Journal of Biochemical and Molecular Toxicology·Romain LasseurEtienne Benoit

Related Concepts

Metazoa
Drug Resistance
Microsomes, Liver
NADH
NADH, NADPH Oxidoreductases
Menaquinone Reductases
Gen-Warfarin
Rats, Laboratory
In Vitro [Publication Type]

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