Profiling serum bile acid glucuronides in humans: Gender divergences, genetic determinants, and response to fenofibrate

J. Trottier, M. Perreault, I. Rudkowska, Cynthia Levy, A. Dallaire-Theroux, M. Verreault, P. Caron, B. Staels, M. C. Vohl, R. J. Straka, O. Barbier

Research output: Contribution to journalArticle

26 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)533-543
Number of pages11
JournalClinical Pharmacology and Therapeutics
Volume94
Issue number4
DOIs
StatePublished - Oct 1 2013
Externally publishedYes

Fingerprint

Fenofibrate
Glucuronides
Bile Acids and Salts
Serum
Chenodeoxycholic Acid
Glucuronosyltransferase
Uridine
Volunteers
Hepatocytes
Genotype
Lipids

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

Profiling serum bile acid glucuronides in humans : Gender divergences, genetic determinants, and response to fenofibrate. / Trottier, J.; Perreault, M.; Rudkowska, I.; Levy, Cynthia; Dallaire-Theroux, A.; Verreault, M.; Caron, P.; Staels, B.; Vohl, M. C.; Straka, R. J.; Barbier, O.

In: Clinical Pharmacology and Therapeutics, Vol. 94, No. 4, 01.10.2013, p. 533-543.

Research output: Contribution to journalArticle

Trottier, J, Perreault, M, Rudkowska, I, Levy, C, Dallaire-Theroux, A, Verreault, M, Caron, P, Staels, B, Vohl, MC, Straka, RJ & Barbier, O 2013, 'Profiling serum bile acid glucuronides in humans: Gender divergences, genetic determinants, and response to fenofibrate', Clinical Pharmacology and Therapeutics, vol. 94, no. 4, pp. 533-543. https://doi.org/10.1038/clpt.2013.122
Trottier, J. ; Perreault, M. ; Rudkowska, I. ; Levy, Cynthia ; Dallaire-Theroux, A. ; Verreault, M. ; Caron, P. ; Staels, B. ; Vohl, M. C. ; Straka, R. J. ; Barbier, O. / Profiling serum bile acid glucuronides in humans : Gender divergences, genetic determinants, and response to fenofibrate. In: Clinical Pharmacology and Therapeutics. 2013 ; Vol. 94, No. 4. pp. 533-543.
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