6-Thiopurine (6TP) is a potent therapeutic agent in the treatment of acute lymphoblastic leukemia. While 6TP has shown great treatment towards this deadly disease, it also has toxicity that prevents its continual administration. The major side effect associated with 6TP treatment is jaundice and hepatotoxicity, both of which comes from increased concentration of bilirubin within the blood. As a result of this deadly toxicity, 6TP need to be administrated in an on- and off-treatment regimen to allow toxicity. Said regimen greatly reduces 6TP effectiveness in the remission of leukemia. Noting that 6TP administration result in the onset jaundice, we hypothesize that this is from the direct inhibition of the enzyme UDP-glucose dehydrogenase, biological enzyme responsible for formation of UDP-glucuronic acid (substrate for bilirubin glucuronides) and hereby decreasing the conjugation of bilirubin to its water-soluble glucuronide form for excretion. To date, we have investigated the 6TP and its oxidative metabolites in regard to inhibition of the various enzymatic steps within the bilirubin excretion pathway both in vitro and in vivo. We have found that UDP-glucose dehydrogenase is inhibited by 6TP and its oxidative metabolites, and that UDP-glucuronosyl transferase enzyme is unaffected. Through understanding how 6TP and its metabolites cause jaundice, structure-activity relationship studies within 6TP can be undertaken that will allow the construction of new class of 6TP compounds with lower, if not eliminated toxicities to be used against leukemia and other cancer through our newly develop delivery vehicles.<br/>

6-Thiopurine: Targeting UDP-glucose dehydrogenase and its efficacy effects

255th National Meeting (2018)

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