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Novel Reductive Pathways for Hydroxywarfarin Metabolism

Graduate #32
Discipline: Chemistry and Chemical Sciences
Subcategory: Biochemistry (not Cell and Molecular Biology and Genetics)

Jasmine Burrell - Jackson State University
Co-Author(s): Dakota Pouncey, Jessica Hartman, and Grover P. Miller, University of Arkansas for Medical Sciences, Little Rock, AR



Coumadin (R/S-warfarin) is a commonly prescribed anticoagulant for over 30 million Americans each year. While highly efficacious, the dose-response for the patient is often unpredictable and poses a therapeutic challenge. Important contributors to unpredictability are variations in R- and S-warfarin metabolism among patients. Warfarin is mainly oxidized by cytochromes P450 into hydroxywarfarins and to a lesser extent reduced by reductases to warfarin alcohols. Despite changes in structure of the parent drugs, warfarin metabolites may contribute to patient dose-responses due to residual pharmacological activity and/or roles in regulating warfarin metabolism. Clearance of primary warfarin metabolites is then likely to have pharmacological importance. Previous studies showed that some hydroxywarfarins can undergo glucuronidation for excretion in urine, but there are other possible routes of elimination for hydroxywarfarins. Like warfarin, we hypothesize that hydroxywarfarins undergo reduction to alcohols as an alternate elimination pathway. We tested this hypothesis by assessing reduction of rac-6-, 7-, 8- and 4’-hydroxywarfarin along with 10-hydroxywarfarin diastereomers using pooled human liver cytosol. We performed control experiments and confirmed reduction of warfarin. Next, we developed HPLC methods to analyze rac-hydroxywarfarin reactions and screened for specific activities. Based on those studies, all five isomeric mixtures of hydroxywarfarins underwent reduction into major and minor alcohols indicating a stereoselective preference for metabolite formation. The highest yields from those reactions were for rac-10- and 4’-hydroxywarfarin while less efficient reduction was observed for rac-6-, 7- and 8-hydroxywarfarin. The modification of the coumarin ring for the latter three hydroxywarfarins then appeared to decrease metabolic efficiency despite its distal location from the site of reduction. Future experiments will confirm the identity of metabolites by MS and reveal the kinetic mechanisms and constants for the reactions. Knowledge gained from those efforts will advance an understanding of the hydroxywarfarin clearance in patients and facilitate studies on their potential clinical relevance.

Not Submitted

Funder Acknowledgement(s): NIH 5R25HL108825-02 (MPI) SURP; NIH P20 GM103429 INBRE; NIH UL1RR029884 UAMS Translational Research Inst. pilot study; AHA 13GRNT1690043 Southwest Affiliate Grant-in-Aid; DGE 1452779 National Science Foundation Graduate Research Fellowship (JHH); HRD 0602740 National Science Foundation LSMAMP Fellowship

Faculty Advisor: Grover P. Miller, MillerGroverP@uams.edu

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This material is based upon work supported by the National Science Foundation (NSF) under Grant No. DUE-1930047. Any opinions, findings, interpretations, conclusions or recommendations expressed in this material are those of its authors and do not represent the views of the AAAS Board of Directors, the Council of AAAS, AAAS’ membership or the National Science Foundation.

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