UDP-glucuronosyltransferase activity in human liver and colon

Background & Aims: The contribution of glucuronidation toward human drug me tabolism is carried out by the Super gene family of UDP-glucuronosyltransfe rases (UGTs). Regulation of the human UGT1A locus is tissue specific, resul ting in the unique expression of multiple hepatic and extrahepatic gene pro ducts. Studies were undertaken to examine UGT1A expression in human hepatic and colonic tissues. Methods: UGT1A messenger RNA, protein, catalytic acti vity, and substrate kinetics were studied in 5 samples of normal hepatic an d sigmoid colon tissue using duplex reverse-transcription polymerase chain reaction (RT-PCR), enzymatic and Western blot analysis, and indirect immuno fluorescence analysis. Results: Specific patterns of UGT1A gene expression occur in the liver and colon, which were consistent with different banding patterns as detected by Western blot analysis using a UGT1A-specific antibo dy. However, microsomal UGT activities in colon were up to 96-fold lower fo r many phenolic substrates, a finding that was not concordant with RT-PCR a nd Western blot analysis. Interestingly, UGT activity toward tertiary amine s and some steroid hormones was equal. Conclusions: Differences of glucuron idation activity between human liver and colon suggest that UGT1A activity may be regulated as a result of the relative presence of individual isoform s with differing catalytic activities or by tissue-specific modulators afte r gene expression.