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首页> 外文期刊>Journal of biochemical and molecular toxicology >Modulation of UDP-glucuronosyltransferase 1A1 in primary human hepatocytes by prototypical inducers.
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Modulation of UDP-glucuronosyltransferase 1A1 in primary human hepatocytes by prototypical inducers.

机译：原型诱导剂对人原代肝细胞中UDP-葡萄糖醛酸转移酶1A1的调节。

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The primary objective of this study was to evaluate the modulation of UGT1A1 expression in human hepatocytes using prototypical CYP450 inducers. A bank of 16 human livers was utilized to obtain an estimate of the range of UGT1A1 protein expression and catalytic activity. Concentration-dependent changes in UGT1A1 response were evaluated in hepatocyte cultures after treatment with 3-methylchloranthrene, beta-napthoflavone, rifampicin, or phenobarbital. Pharmacodynamic analyses of UGT1A1 expression were conducted and compared to those of CYP450 after treatment with inducers in 2-3 different hepatocyte preparations. Additionally, expression of UGT1A1 mRNA and protein was evaluated in human hepatocytes treated with 14 different compounds known to activate differentially the human pregnane-X-receptor or constitutive androstane receptor. Pharmacodynamic modeling revealed EC(50) values statistically significant between UGT1A1 and CYP2B6 after treatment with PB, but not statistically distinguishable between UGT1A1 and CYP's 1A2 or 3A4 after treatment with 3-methylchloranthrene or rifampicin, respectively. UGT1A1 was most responsive to the pregnane-X-receptor-agonists rifampicin, ritonavir, and clotrimazole at the mRNA level and, to a lesser extent, the constitutive androstane receptor-activators, phenobarbital and phenytoin. Pharmacodynamic analyses support a mechanism of coordinate regulation between UGT1A1 and a number of CYP450 enzymes by multiple nuclear receptors. (c) 2005 Wiley Periodicals, Inc. J Biochem Mol Toxicol 19:96-108, 2005; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20058.
机译：这项研究的主要目的是评估使用原型CYP450诱导剂对人肝细胞中UGT1A1表达的调节。利用一组16个人肝来评估UGT1A1蛋白表达范围和催化活性。在使用3-甲基氯蒽，β-萘并黄酮，利福平或苯巴比妥治疗后，在肝细胞培养物中评估了UGT1A1反应的浓度依赖性变化。进行了UGT1A1表达的药效学分析，并与诱导剂处理了2-3种不同肝细胞制剂中的CYP450进行了比较。此外，在用14种已知可差异激活人孕烷X受体或组成型雄烷受体的化合物处理的人肝细胞中，评估了UGT1A1 mRNA和蛋白质的表达。药效动力学模型显示，用PB治疗后，UGT1A1和CYP2B6之间的EC（50）值在统计学上显着，但分别用3-甲基氯蒽或利福平治疗后，UGT1A1和CYP的1A2或3A4之间没有统计学上的区别。 UGT1A1在mRNA水平上对孕烷X受体激动剂rifampicin，利托那韦和克霉唑反应最强，而对组成型雄烷受体激活剂，苯巴比妥和苯妥英钠的反应较小。药效学分析支持UGT1A1与多种CYP450酶之间通过多个核受体进行协调调节的机制。 （c）2005 Wiley Periodicals，Inc. J Biochem Mol Toxicol 19：96-108，2005;在线发布于Wiley InterScience（www.interscience.wiley.com）。 DOI 10.1002 / jbt.20058。

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