Human UDP-glucuronosyltransferases show atypical metabolism of mycophenolic acid and inhibition by curcumin.
Although the promising immunosuppressant, mycophenolic acid (MPA), has many desirable properties and is widely prescribed for organ transplant recipients, its high oral dosage requirement is not understood. Whereas previous Northern blot analysis by Basu and colleagues (2004) located the mRNAs encoding MPA primary metabolizers, UDP-glucuronosyltransferases (UGTs) 1A7, 1A8, 1A9, and 1A10, in human gastrointestinal (GI) tissues, in situ hybridization analysis of mRNAs found that the isozymes were restricted to the mucosal layer of various GI organs. Concomitantly, MPA was glucuronidated by microsomes isolated from normal adjoining specimens. Microsomal studies showed the highest relative rates of metabolism in esophagus, ileum, duodenum, colon, and stomach at pH 6.4; only esophagus showed high pH 7.6 activity. Properties of the recombinant UGTs indicate that MPA is metabolized with pH 6.4 or 7.6 optimum. Activity for 1A7 and 1A9 increased with increasing concentrations up to 2.4 mM, with parallel production of both ether- and acylglucuronides; similarly, 1A8 and 1A10 reached plateaus at 1.6 mM, producing both glucuronides. K(m) values were 250 to 550 microM. Between 400 and 1600 microM MPA, isozymes generated between 15 and 42% of the acylglucuronides. In effect, high K(m) values (MPA) are associated with high concentrations to achieve saturation kinetics. Finally, transient inhibition of UGTs in human LS180 colon cells and mouse duodenum by the dietary agent, curcumin, has implications for in vivo pretreatment to reduce MPA glucuronidation to increase the therapeutic index.
Basu
Nikhil K
NK
Heritable Disorders Branch, National Institute of Child Health and Human Development, National Institutes of Health, Building 10, Room 9S-241, Bethesda, MD 20892-1830, USA.
Kole
Labanyamoy
L
Kubota
Shigeki
S
Owens
Ida S
IS
D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D003106:Colon / Q000378:metabolism; D003474:Curcumin / Q000494:pharmacology*; D004386:Duodenum / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004947:Esophagus / Q000378:metabolism; D005753:Gastric Mucosa / Q000378:metabolism; D041981:Gastrointestinal Tract / Q000201:enzymology / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000378:metabolism*; D006801:Humans; D007082:Ileum / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000378:metabolism* / Q000493:pharmacokinetics; D017403:In Situ Hybridization; D007527:Isoenzymes / Q000378:metabolism; D051379:Mice; D008861:Microsomes / Q000201:enzymology / Q000378:metabolism; D009173:Mycophenolic Acid / Q000378:metabolism* / Q000493:pharmacokinetics; D009928:Organ Specificity
D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D007527:Isoenzymes; D014453:Glucuronosyltransferase; D009173:Mycophenolic Acid; D003474:Curcumin