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.

Increased UGT1A3 and UGT1A7 Expression is Associated with Pancreatic Cancer

“…UGT1A expression was down-regulated in bladder cancer (Izumi et al, 2014). Strassburg et al (2000) reported that the UGT1A isoforms were present in gastrointestinal tissues from individuals but were absent in those from other individuals. Additionally, UGT1A10 mRNA expression levels were correlated with the ethnicity of the donors (Starland-Davenport et al, 2008).…”

Human UGT1A8 and UGT1A10 mRNA Are Expressed In Primary Human Hepatocytes

“…26,30 ) Using the previously published primers (UGT1A8-G), no hepatic expression of UGT1A8 was found prior to our investigations. 8,24,25 ) Our side-by-side comparison using both UGT1A8-C and -1A8-G primers to analyze the expression of UGT1A8 mRNA in the human hepatocytes resulted in the identification of UGT1A8 expression in all the hepatocytes analyzed. In five of the six donors investigated, the mRNA product was only generated using the -1A8-C primers.…”

“…UGT1A8 and -1A10 have been postulated to be exclusively expressed in extrahepatic tissue, 8,12,14,[24][25][26][27] and UGT1A5 was defined as the "missing UGT" since no expression has ever been demonstrated 12 ); however, Finel et al recently identified UGT1A5 mRNA expression in primary human hepatocytes. 23 ) Basal levels of mRNA for this isoform were low; however, significant up-regulation was observed after treatment with Rif and 3-MC.…”

Expression of UGT2B7, a UDP-Glucuronosyltransferase Implicated in the Metabolism of 4-Hydroxyestrone and All-Trans Retinoic Acid, in Normal Human Breast Parenchyma and in Invasive and in Situ Breast Cancers

“…Expression of UGT2B7, like that of other phase II enzymes, is likely to be inducible by endobiotics as well as xenobiotics and in a tissue-specific manner. 1,45,46 Hence, the apparent interindividual differences in level of expression of UGT2B7 could reflect differences in hormonal milieu among patients, as well as in their exposure to xenobiotics and drugs. To begin to interpret the significance of the interindividual differences for cancer susceptibility will require much more knowledge of the regulation of UGT2B7 expression than what is currently available.…”