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  • Title: Mechanistic insights into the effect of CYP2C9*2 and CYP2C9*3 variants on the 7-hydroxylation of warfarin.
    Author: Pavani A, Naushad SM, Stanley BA, Kamakshi RG, Abinaya K, Amaresh Rao M, Uma A, Kutala VK.
    Journal: Pharmacogenomics; 2015; 16(4):393-400. PubMed ID: 25823787.
    Abstract:
    AIM: To evaluate the impact of CYP2C9*2 and CYP2C9*3 variants on binding and hydroxylation of warfarin. MATERIALS & METHODS: Multiple linear regression model of warfarin pharmacokinetics was developed from the dataset of patients (n = 199). Pymol based in silico models were developed for the genetic variants. RESULTS: CYP2C9*2 and CYP2C9*3 variants exhibited high warfarin/7-hydroxywarfarin (multiple linear regression model), dose-dependent disruption of hydrogen bonds with warfarin, dose-dependent increase in the distance between C7 of S-warfarin and Fe-O of CYP2C9, dose-dependent decrease in the glide scores (in silico). CONCLUSION: CYP2C9*2 and CYP2C9*3 variants result in disruption of hydrogen bonding interactions with warfarin and longer distance between C7 and Fe-O thus impairing warfarin 7-hydroxylation due to lower binding affinity of warfarin. Original submitted 7 May 2014; Revision submitted 30 October 2014.
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