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Evaluation of Farnesoid X Receptor Target Gene Induction in Human Hepatocytes: Amino Acid Conjugation

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Background: The nuclear hormone receptor, Farnesoid X Receptor (FXR) regulates the transcription of genes associated with bile acid metabolism and disposition.

Objective: This study investigates possible changes in the expression of target genes responsible for amino acid conjugation, i.e., Bile Acid-CoA Synthetase (BACS) and bile acid-CoA: amino acid Nacetyltransferase (BAT). These genes have been shown to be inducible by FXR agonists in rat models, however, to date no studies have been conducted in a human hepatocyte model.

Results: In human hepatocytes, treatment with the FXR agonists GW4064 (1.0 μM) and WAY362450 (0.1 μM) did not significantly induce the mRNA expression of BACS and BAT genes. However, other target genes associated with FXR activation, such as Bile Salt Export Pump (BSEP), Short Heterodimer Partner (SHP), Multidrug Resistance-associated Protein 2 (MRP2) and Multidrug Resistance Protein 3 (MDR3), were upregulated. Interestingly, a follow up study conducted in rat hepatocytes indicated that GW4064 induced the BACS gene while WAY362450 induced the BAT gene, confirming literature results that these genes can be induced in rat.

Conclusion: In conclusion, there appears to be some species differences in the activation of FXR target genes.
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Keywords: Farnesoid X receptor; amino acid conjugation; bile acid; enzyme induction; hepatocytes; metabolism

Document Type: Research Article

Publication date: June 1, 2017

More about this publication?
  • Drug Metabolism Letters publishes short papers on major advances in all areas of drug metabolism and disposition. The emphasis will be on publishing quality papers very rapidly. Letters will be processed rapidly by taking full advantage of the Internet technology for both the submission and review of manuscripts. The journal covers the following areas:

    In vitro systems including CYP-450; enzyme induction and inhibition; drug-drug interactions and enzyme kinetics; pharmacokinetics, toxicokinetics, species scaling and extrapolations; P-glycoprotein and transport carriers; target organ toxicity and interindividual variability; drug metabolism and disposition studies; extrahepatic metabolism; phase I and phase II metabolism; recent developments for the identification of drug metabolites, reactive intermediate and glutathione conjugates.
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