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

Drug metabolism letters Pub Date : 2017-01-01 DOI:10.2174/1872312812666171227213946

Jean Simmermacher, Michael Sinz

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引用次数: 3

Abstract

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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法脂类X受体靶基因在人肝细胞诱导的评价:氨基酸偶联。

背景:核激素受体Farnesoid X receptor (FXR)调节与胆汁酸代谢和处置相关基因的转录。目的:探讨氨基酸偶联靶基因，即胆汁酸-辅酶a合成酶(BACS)和胆汁酸-辅酶a:氨基酸乙酰转移酶(BAT)表达的可能变化。这些基因已在大鼠模型中被FXR激动剂诱导，然而，迄今为止尚未在人肝细胞模型中进行研究。结果:在人肝细胞中，FXR激动剂GW4064(1.0µM)和WAY362450(0.1µM)未显著诱导BACS和BAT基因的mRNA表达。然而，与FXR激活相关的其他靶基因，如胆汁盐输出泵(BSEP)、短异二聚体伴侣(SHP)、多药耐药相关蛋白2 (MRP2)和多药耐药蛋白3 (MDR3)上调。有趣的是，后续在大鼠肝细胞中进行的研究表明，GW4064诱导BACS基因，WAY362450诱导BAT基因，证实了文献中这些基因在大鼠体内可以诱导的结果。结论:综上所述，FXR靶基因的激活存在一定的物种差异。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Drug metabolism letters Pharmacology, Toxicology and Pharmaceutics-Pharmaceutical Science

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期刊介绍： Drug Metabolism Letters publishes letters and research articles on major advances in all areas of drug metabolism and disposition. The emphasis is on publishing quality papers very rapidly by taking full advantage of the Internet technology both for 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.