Targeted inhibition of glucuronidation markedly improves drug efficacy in mice - a model |
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Authors: | Basu Nikhil K Kole Labanyamoy Basu Mousumi McDonagh Antony F Owens Ida S |
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Institution: | Heritable Disorders Branch, National Institute of Child Health and Human Development, National Institutes of Health, Building 10, Room 8D-42, Bethesda, MD 20892-1830, USA. basun@mail.nih.gov |
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Abstract: | Finding UDP-glucuronosyltransferases (UGT) require protein kinase C-mediated phosphorylation is important information that allows manipulation of this critical system. UGTs glucuronidate numerous aromatic-like chemicals derived from metabolites, diet, environment and, inadvertently, therapeutics to reduce toxicities. As UGTs are inactivated by downregulating PKCs with reversibly-acting dietary curcumin, we determined the impact of gastro-intestinal glucuronidation on free-drug uptake and efficacy using immunosuppressant, mycophenolic acid (MPA), in mice. Expressed in COS-1 cells, mouse GI-distributed Ugt1a1 glucuronidates curcumin and MPA and undergoes irreversibly and reversibly dephosphorylation by PKC-specific inhibitor calphostin-C and general-kinase inhibitor curcumin, respectively, with parallel effects on activity. Moreover, oral curcumin-administration to mice reversibly inhibited glucuronidation in GI-tissues. Finally, successive oral administration of curcumin and MPA to antigen-treated mice increased serum free MPA and immunosuppression up to 9-fold. Results indicate targeted inhibition of GI glucuronidation in mice markedly improved free-chemical uptake and efficacy using MPA as a model. |
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Keywords: | UDP-glucuronosyltransferase Phosphorylation Proof of principle Immunosupression Mycophenolic acid CTL assay Curcumin Calphostin-C PKC Drug efficacy |
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