Human UDP-glucuronosyltransferase (UGT)1A3 enzyme conjugates chenodeoxycholic acid in the liver

Abstract

Chenodeoxycholic acid (CDCA) is a liver-formed detergent and plays an important role in the control of cholesterol homeostasis. During cholestasis, toxic bile acids (BA) accumulate in hepatocytes causing damage and consequent impairment of their function. Glucuronidation, a conjugation reaction catalyzed by UDP-glucuronosyltransferase (UGT) enzymes, is considered an important metabolic pathway for hepatic BA. This study identifies the human UGT1A3 enzyme as the major enzyme responsible for the hepatic formation of the acyl CDCA-24glucuronide (CDCA-24G). Kinetic analyses revealed that human liver and UGT1A3 catalyze the formation of CDCA-24G with similar K m values of 10.6 to 18.6 mol/L, respectively. In addition, electrophoretic mobility shift assays and transient transfection experiments revealed that glucuronidation reduces the ability of CDCA to act as an activator of the nuclear farnesoid X-receptor (FXR). Finally, we observed that treatment of human hepatocytes with fibrates increases the expression and activity of UGT1A3, whereas CDCA has no effect. In conclusion, UGT1A3 is the main UGT enzyme for the hepatic formation of CDCA-24G and glucuronidation inhibits the ability of CDCA to act as an FXR activator. In vitro data also suggest that fibrates may favor the formation of bile acid glucuronides in cholestatic patients.

Glucuronidation of Thyroxine in Human Liver, Jejunum, and Kidney Microsomes

“…The thyroxine glucuronosyltransferase activity in microsomes from 12 human livers ranged from 23.7 to 84.8 pmol/ min/mg protein, representing 3.6-fold variability. Correlation analyses were performed between the thyroxine glucuronosyltransferase activity and typical activities including bilirubin O-glucuronidation catalyzed by UGT1A1, estradiol 3-O-glucuronidation catalyzed by UGT1A1 and UGT1A8 (Lepine et al, 2004), chenodeoxycholic acid 24-O-glucuronidation catalyzed by UGT1A3 (Trottier et al, 2006), imipramine N-glucuronidation catalyzed by UGT1A3 and UGT1A4, serotonin O-glucuronidation catalyzed by UGT1A6, propofol O-glucuronidation catalyzed by UGT1A8 and UGT1A9, or morphine 3-Oglucuronidation catalyzed by UGT2B7 (Table 3). Since UGT1A8 is not expressed in human liver, the estradiol 3-O-and propofol Oglucuronosyltransferase activities represented are the UGT1A1 and UGT1A9 activities, respectively.…”

“…Bilirubin O-glucuronosyltransferase , imipramine N-glucuronosyltransferase , and serotonin O-glucuronosyltransferase (Fujiwara et al, 2007) activities in microsomes from 12 human livers were determined according to methods established in our laboratory. Chenodeoxycholic acid 24-O-glucuronosyltransferase activities in these human liver microsomes were determined according to the method of Trottier et al (2006) with slight modifications. Estradiol 3-O-, propofol O-, and morphine 3-O-glucuronosyltransferase activities in these human liver microsomes were provided by the manufacturer.…”

Bile acid detoxifying enzymes limit susceptibility to liver fibrosis in female SHRSP5/Dmcr rats fed with a high-fat-cholesterol diet

“…Hence, as shown in SHRSP and SHESP5/Dmcr male rats [18], these data suggest the importance of phase II reactions of drug-metabolizing enzymes in NASH/NAFLD progression and differing sensitivities to HFC feeding. UGT and SULT are involved in detoxification of toxic BAs such as CDCA and glyco-formed BAs [36,37], and whereas Ugt1a1 contributes to bilirubin metabolism, Ugt1a3, Ugt2b4, and Ugt2b7 metabolize BA (24-OH), BA (6-OH), and BA (3-OH), respectively, [38][39][40]. With the exceptions of Ugt1a3 and 2b7, the present HFC diet had smaller effects on UGT isoforms in female rats at early stages, and although the roles of Ugt1a6 in BA metabolism remain unknown, this isoform was relatively unaffected by HFC feeding in females.…”

Bile acids in drug induced liver injury: Key players and surrogate markers

“…This may also apply to other species with mixed taurine and glycine conjugation of BAs [13]. Other conjugation reactions such as sulfation and glucuronidation may occur, but are considered less relevant for the elimination of BAs under normal physiological conditions [14][15][16][17][18][19][20].…”

“…Glucuronidation of BAs, for example, appears to be of little relevance under normal physiologic conditions [82]. However, it was reported that glucuronidation may become more important under severe cholestatic conditions, since it allows the conversion of cytotoxic BAs into non-toxic glucuronides, which also facilitates MRP3-mediated alternative efflux from hepatocytes into the blood for urinary elimination [16,[83][84][85]. Sulfation of BAs by sulfotransferase (e.g.…”