CHARACTERIZATION OF 2 UDP GLUCURONOSYLTRANSFERASES THAT ARE PREDOMINANTLY EXPRESSED IN HUMAN COLON

The liver and gastrointestinal tract are major sites of drug metabolis m. However, although the UDP glucuronosyltransferase family of drug-me tabolizing enzymes has been extensively characterized in the liver, li ttle 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 h uman liver. The cDNA encoding these two forms, UGT1A8 and UGT1A10, was synthesized and expressed in COS-7 cells. Both proteins have molecula r masses of 56 kDa and are active towards hydroxylated metabolites of the carcinogens, benzo(alpha)pyrene and a-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-a cetylaminofluorene. Both enzymes were inactive towards the benzo(alpha )pyrene trans 4, 5 and 7, 8 dihydrodiols. In addition, these UDP glucu ronosyltransferases displayed differential activity towards several ph enolic substrates. A survey of human tissues indicated that UGT1A8 and UGT1A10 transcripts are predominantly expressed in the gastrointestin al tract, in contrast to most other UDP glucuronosyltransferase forms which are expressed in the liver and other tissues. These results sugg est that UGT1A8 and UGT1A10 may play an important role in the metaboli sm of dietary xenobiotics. (C) 1998 Academic Press.