Human UDP-glucuronosyltransferases (UGTs) play an important role in the overall metabolism of many endogenous products that are being processed through various catabolic processes as well as substances consumed in the diet or taken as medications. Metabolism by glucuronidation is a process that leads to the eventual biological inactivation and elimination of these substances, with excretion occurring in the bile or urine. The major organ that is thought to facilitate the majority of glucuronidation is the liver, and indeed, research into the cellular and molecular aspects of glucuronidation have focused on the multiplicity and functional properties of the UGTs in liver. However, considerable metabolism takes place in other tissues such as those associated with the gastrointestinal (GI) tract. Progress over the past funding period has lead to the characterization of regulatory patterns of the human UGT1A locus in hepatic and several extrahepatic tissues of the GI tract. This work has lead to the cloning and characterization of three new gene transcripts, UGT1A7, UGT1A8 and UGT1A10, all of which are expressed solely in extrahepatic tissues. Analysis of UGT1A gene transcripts by PCR analysis in human tissues has demonstrated unique patterns of expression in liver, stomach and colon. From these tissues, the nine UGT1A locus gene transcripts have been cloned. The long term goal of this research plan is to characterize the extrahepatic expression of the UGT1A locus as it relates to tissue specificity, structural determinants and gene control. In continuation of experiments in progress the following goals will be advanced; 1) To examine the regulatory pattems of the UGT1A locus in small intestine 2) To develop antibodies and determine if the unique patterns of UGT1A gene expression in extrahepatic tissues corresponds to similar patterns of protein expression. 3) To determine the structural basis for the functional requirements of the extraheptic UGT1A7, UGT1A8 and UGT1A10. 4) To determine the molecular events that control the tissue specific expression patterns of UGT1A7, UGT1A8 and UGT1A10. These studies should provide a better understanding for the cellular and molecular events that underlie the tissue specific expression patterns of the UGT1A locus in human tissues.
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