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首页> 外文期刊>Archives of Toxicology >Novel roles for AhR and ARNT in the regulation of alcohol dehydrogenases in human hepatic cells
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Novel roles for AhR and ARNT in the regulation of alcohol dehydrogenases in human hepatic cells

机译：AHR和ARNT在人肝细胞中酒精脱氢酶调节中的新颖作用

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摘要

The mechanisms by which pollutants participate in the development of diverse pathologies are not completely understood. The pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) activates the AhR (aryl hydrocarbon receptor) signaling pathway. We previously showed that TCDD (25 nM, 30 h) decreased the expression of several alcohol metabolism enzymes (cytochrome P450 2E1, alcohol dehydrogenases ADH1, 4 and 6) in differentiated human hepatic cells (HepaRG). Here, we show that, as rapidly as 8 h after treatment (25 nM TCDD) ADH expression decreased 40 % (p < 0.05). ADH1 and 4 protein levels decreased 40 and 27 %, respectively (p < 0.05), after 72 h (25 nM TCDD). The protein half-lives were not modified by TCDD which suggests transcriptional regulation of expression. The AhR antagonist CH-223191 or AhR siRNA reduced the inhibitory effect of 25 nM TCDD on ADH1A, 4 and 6 expression 50-100 % (p < 0.05). The genomic pathway (via the AhR/ARNT complex) and not the non-genomic pathway involving c-SRC mediated these effects. Other AhR ligands (3-methylcholanthrene and PCB 126) decreased ADH1B, 4 and 6 mRNAs by more than 78 and 55 %, respectively (p < 0.01). TCDD also regulated the expression of ADH4 in the HepG2 human hepatic cell line, in primary human hepatocytes and in C57BL/6J mouse liver. In conclusion, activation of the AhR/ARNT signaling pathway by AhR ligands represents a novel mechanism for regulating the expression of ADHs. These effects may be implicated in the toxicity of AhR ligands as well as in the alteration of ethanol or retinol metabolism and may be associated further with higher risk of liver diseases or/and alcohol abuse disorders.
机译：污染物参与不同病理发展的机制并不完全理解。污染物2,3,7,8-四氯二苯并苯并-P-二恶英（TCDD）活化AHR（芳基烃受体）信号通路。我们以前表明TCDD（25nm，30 h）降低了几种醇代谢酶的表达（细胞色素p450 2e1，醇脱氢酶Adh1,4和6）在分化的人肝细胞（heparg）中。在这里，我们表明，治疗后的8小时（25nm TCDD）ADH表达减少40％（P <0.05）。在72小时（25nm TCDD）之后，ADH1和4蛋白水平分别降低了40％和27％（P <0.05）。 TCDD未修饰蛋白质半衰期，这表明表达的转录调节。 AHR拮抗剂CH-223191或AHR siRNA降低了在ADH1A，4和6表达上的25nm TCDD的抑制作用50-100％（P <0.05）。基因组途径（通过AHR / ARNT复合物）而不是涉及C-SRC介导的非基因组途径。其他AHR配体（3-甲基蒽和PCB 126）分别降低了AdH1b，4和6 mRNA，分别超过78％和55％（P <0.01）。 TCDD还调节在HepG2人肝细胞系中ADH4的表达，在原发性人肝细胞和C57BL / 6J小鼠肝脏中。总之，AHR配体的AHR / ARNT信号传导途径的激活代表了调节ADHS表达的新机制。这些效果可以涉及AHR配体的毒性以及在乙醇或视黄醇代谢的改变中，并且可以进一步相关，肝脏疾病或/和酒精滥用疾病的风险较高。

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