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Inhibition of UDP-glucose dehydrogenase by analogs of 6-thiopurine.


It has been demonstrated that jaundice results in a substantial number of leukemia patients following treatment with the antineoplastic agent 6-thiopurine. Jaundice can result due to an inability to efficiently excrete bilirubin due to a lack of glucuronide conjugation. Bilirubin conjugation can be inhibited due to a decrease in UDP-glucuronide concentration. The cellular concentration of UDP-glucuronide is determined by the activity of UDP-glucose dehydrogenase that catalyzes the conversion of UDP-glucose to UDP-glucuronide. We have developed an HPLC method for assessing the activiy of the enzyme UDP-glucose dehydrogenase. With this method, we have demonstrated that the enzyme UDP-glucose dehydrogenase can be inhibited in vitro by 6-thiopurine and its major metabolite 6-thiouric acid. Kinetic studies have indicated that the inhibition may be physiologically relevant. An approach has been taken to synthesize analogs of 6-thiopurine that have pharmacologic activity but do not inhibit the activity of UDP-glucose dehydrogenase. The kinetic results of the synthetic analogs of 6-thiopurine will be reported along with the details of the HPLC method. Analogs demonstrating little or no inhibition of this enzyme will be further tested for pharmacological activity.

Victoria L. Esquibel and Richard M. Hyslop *. Department of Chemistry & Biochemistry, University of Northern Colorado.

* Denotes membership in the Colorado-Wyoming Academy of Science.
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Author:Esquibel, Victoria L.; Hyslop, Richard M.
Publication:Journal of the Colorado-Wyoming Academy of Science
Article Type:Brief Article
Geographic Code:1USA
Date:Apr 1, 2001
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