Differential and special properties of the major human UGT1-encoded gastrointestinal UDP-glucuronosyltransferases enhance potential to control chemical uptake

J Biol Chem. 2004 Jan 9;279(2):1429-41. doi: 10.1074/jbc.M306439200. Epub 2003 Oct 13.


UDP-glucuronosyltransferase (UGT) isozymes detoxify metabolites, drugs, toxins, and environmental chemicals via conjugation to glucuronic acid. Based on the extended UGT1 locus combined with Northern blot analysis and in situ hybridization, we determined the distribution of UGT1A1 and UGT1A7 through UGT1A10 mRNAs and found them for the first time segmentally distributed in the mucosal epithelia layer of the gastrointestinal tract. Biochemically, recombinant isozymes exhibited pH optima of 5.5, 6.4, 7.6, 8.5, and/or a broad pH range, and activities were found to be unaffected or progressively inhibited by increasing substrate concentrations after attaining Vmax for certain chemicals. Under different optimal conditions, all exhibited wide substrate selections for dietary and environmentally associated chemicals. Evidence also suggests tandem effects of isozymes in the time for completion of reactions when comparing short- and long-term incubations. Moreover, treatment of colon cells with certain diet-associated constituents, curcumin and nordihydroguaiaretic acid, reversibly targets UGTs causing inhibition without affecting protein levels; there is no direct inhibition of control UGT using curcumin as substrate in the in vitro assay. In summary, we demonstrate that UGTs are located in gastrointestinal mucosa, have vast overlapping activities under differential optimal conditions, and exhibit marked sensitivity to certain dietary substrates/constituents, representing a first comprehensive study of critical properties concerning glucuronidating isozymes in alimentary tissues. Additionally, the highly dynamic, complex, and variable properties necessarily impact absorption of ingested chemicals and therapeutic drugs.

MeSH terms

  • Animals
  • Blotting, Northern
  • COS Cells
  • Cell Line
  • Cell Line, Tumor
  • Cell Survival
  • Colonic Neoplasms / metabolism
  • Curcumin / pharmacology
  • DNA, Complementary / metabolism
  • Digestive System / metabolism
  • Dose-Response Relationship, Drug
  • Epithelial Cells / metabolism
  • Glucuronosyltransferase / biosynthesis*
  • Humans
  • Hydrogen-Ion Concentration
  • In Situ Hybridization
  • Kinetics
  • Masoprocol / pharmacology
  • Microsomes / metabolism
  • Models, Chemical
  • Mucous Membrane / metabolism
  • Protein Isoforms
  • RNA, Messenger / metabolism
  • Recombinant Proteins / metabolism
  • Substrate Specificity
  • Time Factors
  • Tissue Distribution
  • Transfection
  • UDP-Glucuronosyltransferase 1A9


  • DNA, Complementary
  • Protein Isoforms
  • RNA, Messenger
  • Recombinant Proteins
  • Masoprocol
  • UGT1A1 enzyme
  • bilirubin uridine-diphosphoglucuronosyl transferase 1A10
  • Glucuronosyltransferase
  • UDP-Glucuronosyltransferase 1A9
  • UDP-glucuronosyltransferase, UGT1A7
  • UDP-glucuronosyltransferase, UGT1A8
  • Curcumin