Human UDP-glucuronosyltransferase (UGT)1A3 enzyme conjugates chenodeoxycholic acid in the liver.
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 mumol/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.
Trottier
Jocelyn
J
Molecular Endocrinology and Oncology Research Center, CHUL Research Center and the faculty of pharmacy, Laval University, Québec, Canada.
Verreault
Mélanie
M
Grepper
Susan
S
Monté
Didier
D
Bélanger
Julie
J
Kaeding
Jenny
J
Caron
Patrick
P
Inaba
Ted T
TT
Barbier
Olivier
O
D000328:Adult; D002460:Cell Line; D002635:Chenodeoxycholic Acid / Q000378:metabolism*; D002995:Clofibric Acid / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D014453:Glucuronosyltransferase / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000201:enzymology*; D008297:Male; D008830:Microbodies; D008862:Microsomes, Liver / Q000378:metabolism; D008875:Middle Aged; D047493:PPAR alpha / Q000378:metabolism; D011743:Pyrimidines / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D000099150:Receptor, Farnesoid X-Activated
D002635:Chenodeoxycholic Acid; D002995:Clofibric Acid; D004268:DNA-Binding Proteins; D014453:Glucuronosyltransferase; D047493:PPAR alpha; D011743:Pyrimidines; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C006253:pirinixic acid; C122075:UDP-glucuronosyltransferase, UGT1A3