title: Targeted inhibition of glucuronidation markedly improves drug efficacy in mice - a model.
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.
authors.affiliation: 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
authors.forename: Nikhil K
authors.initials: NK
authors.lastname: Basu
authors.forename: Labanyamoy
authors.initials: L
authors.lastname: Kole
authors.forename: Mousumi
authors.initials: M
authors.lastname: Basu
authors.forename: Antony F
authors.initials: AF
authors.lastname: McDonagh
authors.forename: Ida S
authors.initials: IS
authors.lastname: Owens
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D003474:Curcumin / Q000008:administration & dosage*; D004195:Disease Models, Animal; D016503:Drug Delivery Systems / Q000379:methods*; D004382:Duodenitis / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology*; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors*; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D051379:Mice; D009173:Mycophenolic Acid; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome
chemical_list: D007166:Immunosuppressive Agents; D014453:Glucuronosyltransferase; D011493:Protein Kinase C; D009173:Mycophenolic Acid; D003474:Curcumin