title: Metabolic profiling of HepG2 cells incubated with S(-) and R(+) enantiomers of anti-coagulating drug warfarin.
abstract: Warfarin is a commonly prescribed oral anticoagulant with narrow therapeutic index. It achieves anti-coagulating effects by interfering with the vitamin K cycle. Warfarin has two enantiomers, S(-) and R(+) and undergoes stereoselective metabolism, with the S(-) enantiomer being more effective. We reported the intracellular metabolic profile in HepG2 cells incubated with S(-) and R(+) warfarin by GCMS. Chemometric method PCA was applied to analyze the individual samples. A total of 80 metabolites which belong to different categories were identified. Two batches of experiments (with and without the presence of vitamin K) were designed. In samples incubated with S(-) and R(+) warfarin, glucuronic acid showed significantly decreased in cells incubated with R(+) warfarin but not in those incubated with S(-) warfarin. It may partially explain the lower bio-activity of R(+) warfarin. And arachidonic acid showed increased in cells incubated with S(-) warfarin but not in those incubated with R(+) warfarin. In addition, a number of small molecules involved in γ-glutamyl cycle displayed ratio variations. Intracellular glutathione detection further validated the results. Taken together, our findings provided molecular evidence on a comprehensive metabolic profile on warfarin-cell interaction which may shed new lights on future improvement of warfarin therapy. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11306-010-0262-3) contains supplementary material, which is available to authorized users.
authors.forename: Jing
authors.initials: J
authors.lastname: Bai
authors.forename: Ming Xuan
authors.initials: MX
authors.lastname: Wang
authors.forename: Balram
authors.initials: B
authors.lastname: Chowbay
authors.forename: Chi Bun
authors.initials: CB
authors.lastname: Ching
authors.forename: Wei Ning
authors.initials: WN
authors.lastname: Chen