title: Profiling serum bile acid glucuronides in humans: gender divergences, genetic determinants, and response to fenofibrate.
abstract: Glucuronidation, catalyzed by uridine 5'-diphospho-glucuronosyltransferase (UGT) enzymes, detoxifies cholestatic bile acids (BAs). We aimed to (i) characterize the circulating BA-glucuronide (BA-G) pool composition in humans, (ii) determine how sex and UGT polymorphisms influence this composition, and (iii) analyze the effects of the lipid-lowering drug fenofibrate on the circulating BA-G profile in 300 volunteers and 5 cholestatic patients. Eleven BA-Gs were determined in pre- and postfenofibrate samples. Men exhibited higher BA-G concentrations, and various genotype/BA-G associations were discovered in relevant UGT genes. The chenodeoxycholic acid-3G (CDCA-3G) concentration was associated with the UGT2B7 802C>T polymorphism. Glucuronidation assays confirmed the predominant role of UGT2B7 and UGT1A4 in CDCA-3G formation. Fenofibrate exposure increased the serum levels of five BA-G species, including CDCA-3G, and upregulated expression of UGT1A4, but not UGT2B7, in hepatic cells. This study demonstrated that fenofibrate stimulates BA glucuronidation in humans and thus reduces BA toxicity in the liver.
authors.affiliation: Laboratory of Molecular Pharmacology, Endocrinology, and Nephrology, CHU-Québec Research Centre and the Faculty of Pharmacy, Laval University, Quebec City, Québec, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Trottier
authors.forename: M
authors.initials: M
authors.lastname: Perreault
authors.forename: I
authors.initials: I
authors.lastname: Rudkowska
authors.forename: C
authors.initials: C
authors.lastname: Levy
authors.forename: A
authors.initials: A
authors.lastname: Dallaire-Theroux
authors.forename: M
authors.initials: M
authors.lastname: Verreault
authors.forename: P
authors.initials: P
authors.lastname: Caron
authors.forename: B
authors.initials: B
authors.lastname: Staels
authors.forename: M-C
authors.initials: MC
authors.lastname: Vohl
authors.forename: R J
authors.initials: RJ
authors.lastname: Straka
authors.forename: O
authors.initials: O
authors.lastname: Barbier
mesh_terms: D001647:Bile Acids and Salts / Q000097:blood*; D002779:Cholestasis / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology; D005260:Female; D011345:Fenofibrate / Q000494:pharmacology* / Q000627:therapeutic use; D005786:Gene Expression Regulation / Q000187:drug effects; D020719:Glucuronides / Q000097:blood*; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D047493:PPAR alpha / Q000819:agonists; D020025:Peroxisome Proliferators / Q000494:pharmacology; D011110:Polymorphism, Genetic / Q000235:genetics; D011743:Pyrimidines / Q000494:pharmacology; D012727:Sex Characteristics
chemical_list: D001647:Bile Acids and Salts; D020719:Glucuronides; D000960:Hypolipidemic Agents; D047493:PPAR alpha; D020025:Peroxisome Proliferators; D011743:Pyrimidines; C019787:bilirubin glucuronoside glucuronosyltransferase; C006253:pirinixic acid; C491474:UGT2B7 protein, human; D014453:Glucuronosyltransferase; D011345:Fenofibrate