Genetic and Structural Determinants of Warfarin and Losartan Binding to Cytochrome P450 2C9

Project: Research

Investigators

  • Manish B Shah (PI)

Description

Warfarin is a well known anti-coagulant agent commonly used in the treatment and prevention of stroke and many other cardiovascular diseases. The more potent S-enantiomer of warfarin is predominantly metabolized by human cytochrome P450 (CYP) 2C9 to 7'-hydroxy warfarin. Genetic variations in the CYP2C9 gene has resulted in decreased warfarin hydroxylation leading to inter-individual differences in warfarin response, drug interactions and adverse reactions. Furthermore, the prodrug losartan is an angiotensin II receptor antagonists used in hypertension. CYP2C9 and CYP3A4 are the two enzymes responsible for metabolic activation of losartan. Significantly high plasma levels of warfarin and losartan were found in patients carrying CYP2C9*2 and *3 alleles as a result of reduced activity of the enzyme. Using x-ray crystallography and isothermal titration calorimetry, the aim is to determine the effect of amino acid substitution in decreased warfarin and losartan hydroxylation acitvity by the two most prevalent CYP2C9 variants,*2 and *3, as well as the two rare variants *5 and *28 of this enzyme. Understanding the molecular determinants of drug interactions to these polymorphic variants may lead to development of safer medications tailored to individual's genetic trait. The significance of the work is that it will yield new and important information that is necessary to understand pharmacogenetics of cardiovascular diseases, which in turn may lead to development of better therapeutics with improved outcomes in patients with defective alleles.
Award amount$154,000.00
Award date01/01/2019
Program typeAHA Institutional Research Enhancement Award (AIRE
Award ID19AIREA34450040
Effective start/end date01/01/201906/30/2021
StatusActive