Telmisartan potentiates the ITE-induced aryl hydrocarbon receptor activity in human liver cell line.

IF 4.8 2区 医学 Q1 TOXICOLOGY Archives of Toxicology Pub Date : 2024-10-31 DOI:10.1007/s00204-024-03901-4
Jiun Hsu, Hsiao-Ho Fang, Jyan-Gwo Joseph Su
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Abstract

Telmisartan is an angiotensin receptor blocker (ARB) approved by the Food and Drug Administration of the US for the treatment of hypertension. It possesses unique pharmacologic properties, including the longest half-life among all ARBs; this leads to a 24-h sustained reduction of blood pressure. Besides well-known antihypertensive and cardioprotective effects, there is also strong clinical evidence that telmisartan confers renoprotection. Aryl hydrocarbon receptor (AhR) belongs to the steroid receptor family. 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) is an endogenous ligand of AhR. Cytochrome P450 (CYP) 1A1 is an AhR-target gene. In this article, we demonstrated that telmisartan (2.5-60 μM) enhanced CYP1A1 promoter activity and expressions of mRNA and protein. Telmisartan-induced CYP1A1 expression was blocked by the AhR antagonist CH-223191 in liver cell lines and was negligible in the AhR signaling-deficient mutant cells. In addition, telmisartan induced transcriptional activity mediated by aryl hydrocarbon response element in both human and mouse cells, and was able to induce AhR translocation into the nucleus. Accordingly, telmisartan is an AhR agonist. It also acted synergistically with ITE to further enhance the expression of CYP1A1 mRNA and protein. This synergistic effect was more pronounced in cells with AhR overexpression compared to those without. AhR activity has strong association with the progression of chronic renal disease. Our study demonstrated that telmisartan is an AhR agonist and has synergistic effect with ITE, an indole derivative, to potentiate the effect on AhR. This finding may provide additional clues about the mechanism of the protective effect of telmisartan on the kidney.

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替米沙坦能增强 ITE 诱导的人肝细胞系芳香烃受体的活性。
替米沙坦是一种血管紧张素受体阻滞剂(ARB),已被美国食品药品管理局批准用于治疗高血压。它具有独特的药理特性,包括在所有血管紧张素受体阻滞剂中具有最长的半衰期,从而可实现 24 小时持续降压。除了众所周知的降压和心脏保护作用外,临床上也有确凿证据表明替米沙坦具有肾脏保护作用。芳基烃受体(AhR)属于类固醇受体家族。2-(1'H-吲哚-3'-羰基)-噻唑-4-羧酸甲酯(ITE)是AhR的内源性配体。细胞色素 P450(CYP)1A1 是 AhR 的靶基因。在本文中,我们证实替米沙坦(2.5-60 μM)可增强 CYP1A1 启动子的活性以及 mRNA 和蛋白质的表达。在肝细胞系中,替米沙坦诱导的CYP1A1表达被AhR拮抗剂CH-223191阻断,而在AhR信号缺失的突变细胞中则可忽略不计。此外,替米沙坦还能在人和小鼠细胞中诱导由芳基烃反应元件介导的转录活性,并能诱导 AhR 转位至细胞核。因此,替米沙坦是一种 AhR 激动剂。替米沙坦还与 ITE 起协同作用,进一步提高 CYP1A1 mRNA 和蛋白质的表达。与未表达 AhR 的细胞相比,这种协同作用在 AhR 过表达的细胞中更为明显。AhR 活性与慢性肾病的进展密切相关。我们的研究表明,替米沙坦是一种AhR激动剂,与吲哚衍生物ITE具有协同作用,可增强对AhR的影响。这一发现可能为替米沙坦对肾脏的保护作用机制提供了更多线索。
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
Archives of Toxicology
Archives of Toxicology 医学-毒理学
CiteScore
11.60
自引率
4.90%
发文量
218
审稿时长
1.5 months
期刊介绍: Archives of Toxicology provides up-to-date information on the latest advances in toxicology. The journal places particular emphasis on studies relating to defined effects of chemicals and mechanisms of toxicity, including toxic activities at the molecular level, in humans and experimental animals. Coverage includes new insights into analysis and toxicokinetics and into forensic toxicology. Review articles of general interest to toxicologists are an additional important feature of the journal.
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