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Secreted protein profile from HepG2 cells incubated by S(−) and R(+) enantiomers of chiral drug warfarin – An analysis in cell‐based system and clinical samples
Author(s) -
Bai Jing,
Ching Chi Bun,
Chowbay Balram,
Chen Wei Ning
Publication year - 2010
Publication title -
proteomics – clinical applications
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.948
H-Index - 54
eISSN - 1862-8354
pISSN - 1862-8346
DOI - 10.1002/prca.201000027
Subject(s) - warfarin , pharmacology , chemistry , cyp2c9 , enantiomer , therapeutic index , fibrinogen , drug , biochemistry , medicine , metabolism , stereochemistry , atrial fibrillation , cytochrome p450
Purpose: Warfarin is a commonly prescribed oral anticoagulant with narrow therapeutic index. It interferes with the vitamin K cycle to achieve anti‐coagulating effects. Warfarin has two enantiomers, S(−) and R(+) and undergoes stereoselective metabolism, with the S(−) enantiomer being more effective. Our target is to discover the biological differences of the two enantiomers for better warfarin therapy. Experimental design: We reported the extracellular protein profile in HepG2 cells incubated with S(−) and R(+) warfarin, using iTRAQ‐coupled 2‐D LC‐MS/MS. In addition, clinical sera from 30 patients taken warfarin were also analyzed by the same method as a long‐term batch. Results: In cell line batch in samples incubated with S(−) and R(+) warfarin alone, inter‐α‐trypsin inhibitor heavy chain H4, apolipoprotein A‐I and α‐2‐HS‐glycoprotein showed variations in cells incubated with S(−) warfarin and R(+) warfarin. For other proteins like α‐2‐macroglobulin and Fibrinogen γ chain, the expressions each were found to be the same in cells incubated with either S(−) or R(+) warfarin. Clinical results showed the same trends for protein ratio changes. Conclusion and clinical relevance: Our results indicated that those proteins may interfere with blood coagulation process, as well as contribute to the warfarin's side‐effect response. Taken together, our findings provided molecular evidence on a comprehensive protein profile on warfarin–cell interaction which may shed new lights on future improvement of warfarin therapy.