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Previous studies have shown that several endogenous compounds, such as bilirubin and certain bile acids, are glucosidated in human liver. In this work, we have identified human UDP-glucuronosyltransferase 2B7 (UGT2B7) as the isoform that catalyzes the glucosidation of hyodeoxycholic acid (HDCA). The glucosidation by UGT2B7 was specific for HDCA and was not observed with the other bile acids examined, lithocholic acid, chenodeoxycholic acid, and ursodeoxycholic acid. The kinetics of HDCA glucuronidation and glucosidation by UGT2B7 were characterized. The Km values for glucuronidation and glucosidation of HDCA were 11.6 and 17.9 μM, respectively, with Vmax values of 4.15 nmol/min/mg protein for glucuronidation and 3.28 nmol/min/mg for glucosidation. At a fixed concentration of HDCA, the apparent Km for UDP-glucuronic acid was 89 μM with a Vmax of 3.53 nmol/min/mg. The corresponding parameters for UDP-glucose were 442 μM and 1.98 nmol/min/mg, respectively. UGT2B7 catalyzed the addition of the glucose and glucuronic acid moieties to an hydroxyl group on HDCA and also possessed some capacity to use UDP-xylose as sugar donor. The two polymorphic variants of UGT2B7, UGT2B7*1 and UGT2B7*2 could both glucosidate HDCA. This is the first report that identifies UGT2B7 as the enzyme responsible for the glucosidation of the bile acid, HDCA. [Copyright &y& Elsevier]

Abstract: Limited studies have been carried out on the biotransformation of carboxyl nonsteroidal anti-inflammatory drugs (NSAIDs) in the liver. However, the role of the intestine in NSAID metabolism has not been investigated. In this report, the contribution of UDP-glucuronosyltransferases (UGTs) in the human gastrointestinal (GI) tract from five donors to the glucuronidation of the NSAIDs, RS-ketoprofen, S-naproxen, RS- and S-etodolac, was investigated. UGT activity and, for some donors, mRNA levels were evaluated. All NSAIDs were glucuronidated throughout the GI tract; however, glucuronidation was low in stomach and duodenum as compared to the remainder of the intestine. RT-PCR analysis demonstrated that the UGT1A isoforms, UGT1A3, 1A8, and 1A10, and UGT2B7 were expressed in the GI tract. Human recombinant UGT1A3, 1A9, 1A10 and 2B7 were actively involved in the glucuronidation of all NSAIDs while UGT1A7 and the intestine-specific UGT1A8 had no glucuronidating activity towards those compounds. Despite interindividual variations in both the levels of mRNA and the distribution of activity through the intestine, UGTs in the GI tract may contribute significantly to the first pass metabolism of orally administered NSAIDs. [Copyright &y& Elsevier]

The regulation of drug-metabolizing enzymes and transporters has an important role in drug metabolism and many human diseases. The genes that encode these enzymes and transporters are inducible by numerous xenobiotics and endobiotics and the inducibility shows clear species specificity. In the past 4–5 years, orphan nuclear receptors such as PXR and CAR have been established as species-specific xeno-sensors that regulate the expression of many detoxifying enzymes and transporters. Their identification represents a major step forward in understanding the pharmacological and genetic control of the expression of drug-metabolizing enzymes and the implication of this regulation in drug metabolism, drug–drug interactions, and human diseases. [Copyright &y& Elsevier]