title: Polymorphic gene regulation and interindividual variation of UDP-glucuronosyltransferase activity in human small intestine.
abstract: UDP-glucuronosyltransferases (UGTs) convert dietary constituents, drugs, and environmental mutagens to inactive hydrophilic glucuronides. Recent studies have shown that the expression of the UGT1 and UGT2 gene families is regulated in a tissue-specific fashion. Human small intestine represents a major site of resorption of dietary constituents and orally administered drugs and plays an important role in extrahepatic UGT directed metabolism. Expression of 13 UGT1A and UGT2B genes coupled with functional and catalytic analyses were studied using 18 small intestinal and 16 hepatic human tissue samples. Hepatic expression of UGT gene transcripts was without interindividual variation. In contrast, a polymorphic expression pattern of all the UGT genes was demonstrated in duodenal, jejunal, and ileal mucosa, with the exception of UGT1A10. To complement these studies, interindividual expression of UGT proteins and catalytic activities were also demonstrated. Hyodeoxycholic acid glucuronidation, catalyzed primarily by UGT2B4 and UGT2B7, showed a 7-fold interindividual variation in small intestinal duodenal samples, in contrast to limited variation in the presence of 4-methylumbelliferone, a substrate glucuronidated by most UGT1A and UGT2B gene products. Linkage of RNA expression patterns to protein abundance were also made with several mono-specific antibodies to the UGTs. These results are in contrast to a total absence of polymorphic variation in gene expression, protein abundance, and catalytic activity in liver. In addition, the small intestine exhibits considerable catalytic activity toward most of the different classes of substrates accepted for glucuronidation by the UGTs, which is supported by immunofluorescence analysis of UGT1A protein in the mucosal cell layer of the small intestine. Thus, tissue-specific and interindividual polymorphic regulation of UGT1A and UGT2B genes in small intestine is identified and implicated as molecular biological determinant contributing to interindividual prehepatic drug and xenobiotic metabolism in humans.
authors.affiliation: Department of Gastroenterology and Hepatology, Hannover Medical School, 30625 Hannover, Germany. strassburg.christian@mh-hannover.de
authors.forename: C P
authors.initials: CP
authors.lastname: Strassburg
authors.forename: S
authors.initials: S
authors.lastname: Kneip
authors.forename: J
authors.initials: J
authors.lastname: Topp
authors.forename: P
authors.initials: P
authors.lastname: Obermayer-Straub
authors.forename: A
authors.initials: A
authors.lastname: Barut
authors.forename: R H
authors.initials: RH
authors.lastname: Tukey
authors.forename: M P
authors.initials: MP
authors.lastname: Manns
mesh_terms: D015153:Blotting, Western; D019084:Fluorescent Antibody Technique, Indirect; D015971:Gene Expression Regulation, Enzymologic; D020719:Glucuronides / Q000096:biosynthesis; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D006923:Hymecromone / Q000378:metabolism; D007413:Intestinal Mucosa / Q000166:cytology / Q000201:enzymology; D007421:Intestine, Small / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000201:enzymology; D008861:Microsomes / Q000201:enzymology; D011110:Polymorphism, Genetic / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015262:Xenobiotics / Q000378:metabolism
chemical_list: D020719:Glucuronides; D007527:Isoenzymes; D012333:RNA, Messenger; D015262:Xenobiotics; D006923:Hymecromone; D014453:Glucuronosyltransferase