Targeted inhibition of glucuronidation markedly improves drug efficacy in mice - a model

Biochem Biophys Res Commun. 2007 Aug 17;360(1):7-13. doi: 10.1016/j.bbrc.2007.05.224. Epub 2007 Jun 14.


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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • COS Cells
  • Chlorocebus aethiops
  • Curcumin / administration & dosage*
  • Disease Models, Animal*
  • Drug Delivery Systems / methods*
  • Duodenitis / chemically induced
  • Duodenitis / drug therapy*
  • Duodenitis / immunology*
  • Glucuronosyltransferase / antagonists & inhibitors*
  • Immunosuppressive Agents / administration & dosage
  • Mice
  • Mycophenolic Acid
  • Protein Kinase C / antagonists & inhibitors*
  • Treatment Outcome


  • Immunosuppressive Agents
  • Glucuronosyltransferase
  • Protein Kinase C
  • Mycophenolic Acid
  • Curcumin