Characterization of two UDP glucuronosyltransferases that are predominantly expressed in human colon.
The liver and gastrointestinal tract are major sites of drug metabolism. However, although the UDP glucuronosyltransferase family of drug-metabolizing enzymes has been extensively characterized in the liver, little is known about this family in the gastrointestinal tract. In this work, an analysis of human colon RNA samples revealed the presence of two UDP glucuronosyltransferase forms that could not be detected in human liver. The cDNA encoding these two forms, UGT1A8 and UGT1A10, was synthesized and expressed in COS-7 cells. Both proteins have molecular masses of 56 kDa and are active towards hydroxylated metabolites of the carcinogens, benzo(alpha)pyrene and 2-acetylaminofluorene. UGT1A8 was most active towards the 10- and 11-hydroxy benzo(alpha)pyrenes and the preferred 2-acetylaminofluorene metabolites were the 1-, 2-, and 8-hydroxy derivatives. UGT1A10 was most active towards the 11- and 12-hydroxybenzo(alpha)pyrenes and the 1- and 3-hydroxy derivatives of 2-acetylaminofluorene. Both enzymes were inactive towards the benzo(alpha)pyrene trans 4, 5 and 7, 8 dihydrodiols. In addition, these UDP glucuronosyltransferases displayed differential activity towards several phenolic substrates. A survey of human tissues indicated that UGT1A8 and UGT1A10 transcripts are predominantly expressed in the gastrointestinal tract, in contrast to most other UDP glucuronosyltransferase forms which are expressed in the liver and other tissues. These results suggest that UGT1A8 and UGT1A10 may play an important role in the metabolism of dietary xenobiotics.
Mojarrabi
B
B
Department of Clinical Pharmacology, Flinders University School of Medicine, Flinders Medical Centre, Australia.
Mackenzie
P I
PI
D000818:Animals; D001564:Benzo(a)pyrene / Q000031:analogs & derivatives / Q000378:metabolism; D019556:COS Cells; D003001:Cloning, Molecular; D003106:Colon / Q000201:enzymology*; D005449:Fluorenes / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics; D014453:Glucuronosyltransferase / Q000737:chemistry*; D006801:Humans; D010636:Phenols / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry; D013379:Substrate Specificity; D015262:Xenobiotics / Q000378:metabolism
D005449:Fluorenes; D010636:Phenols; D012333:RNA, Messenger; D011994:Recombinant Proteins; D015262:Xenobiotics; D001564:Benzo(a)pyrene; D014453:Glucuronosyltransferase