饮用水中的砷对小鼠肠道微粒体环氧化物水解酶表达和活性的诱导作用具有组织、区域和基因特异性。

IF 4.4 3区 医学 Q1 PHARMACOLOGY & PHARMACY
Hui Li, Xiaoyu Fan, Xinxin Ding, Qing-Yu Zhang
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引用次数: 0

摘要

本研究旨在描述砷暴露对肝脏和小肠中微粒体环氧化物水解酶(mEH 或 Ephx1)和可溶性环氧化物水解酶(sEH 或 Ephx2)表达的影响。C57BL/6 小鼠在不同剂量的饮用水中接触亚砷酸钠长达 28 天。在 25 ppm 的砷浓度下,雄性和雌性小鼠的肠道 mEH mRNA 和蛋白质表达受到诱导,而肝脏 mEH 的表达则受到 50 或 100 ppm 砷浓度的诱导。mEH 的诱导具有基因特异性,因为砷暴露不会诱导 sEH 在这两种组织中的表达。在小肠中,mEH 只在近端而不是远端被诱导表达。在诱导肠道 mEH 的同时,体外微粒体酶对 mEH 模型底物顺式氧化二苯乙烯和含环氧化物药物奥罗佐米的活性也有所提高,奥罗佐米治疗小鼠近端小肠中奥罗佐米的主要水解代谢产物 PR-176 的水平也有所提高。这些研究结果表明,肠道 mEH(在将异生物环氧化物转化为活性较低的二元醇过程中发挥主要作用)而 sEH(更喜欢将内源性环氧化物作为底物)与砷暴露的不良影响有关,因此有必要进一步研究饮用水砷暴露与含环氧化物药物及其他异生物化合物在肠道中的处置或可能产生的不良影响之间的相互作用。意义声明 饮用受砷污染的水与人类罹患糖尿病等各种不良健康影响的风险增加有关。小肠上皮细胞是吸收摄入砷的主要部位,但它们在砷暴露相关变化方面的特征并不明显。这项研究确定了小肠中的基因表达变化,这些变化可能与砷暴露的不良影响以及砷摄入与体内含环氧化物药物的药代动力学之间可能存在的相互作用存在机理上的联系。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Tissue-, Region-, and Gene-Specific Induction of Microsomal Epoxide Hydrolase Expression and Activity in the Mouse Intestine by Arsenic in Drinking Water.

This study aimed to characterize the effects of arsenic exposure on the expression of microsomal epoxide hydrolase (mEH or EPHX1) and soluble epoxide hydrolase (sEH or EPHX2) in the liver and small intestine. C57BL/6 mice were exposed to sodium arsenite in drinking water at various doses for up to 28 days. Intestinal, but not hepatic, mEH mRNA and protein expression was induced by arsenic at 25 ppm, in both males and females, whereas hepatic mEH expression was induced by arsenic at 50 or 100 ppm. The induction of mEH was gene specific, as the arsenic exposure did not induce sEH expression in either tissue. Within the small intestine, mEH expression was induced only in the proximal, but not the distal segments. The induction of intestinal mEH was accompanied by increases in microsomal enzymatic activities toward a model mEH substrate, cis-stilbene oxide, and an epoxide-containing drug, oprozomib, in vitro, and by increases in the levels of PR-176, the main hydrolysis metabolite of oprozomib, in the proximal small intestine of oprozomib-treated mice. These findings suggest that intestinal mEH, playing a major role in converting xenobiotic epoxides to less reactive diols, but not sEH, preferring endogenous epoxides as substrates, is relevant to the adverse effects of arsenic exposure, and that further studies of the interactions between drinking water arsenic exposure and the disposition or possible adverse effects of epoxide-containing drugs and other xenobiotic compounds in the intestine are warranted. SIGNIFICANCE STATEMENT: Consumption of arsenic-contaminated water has been associated with increased risks of various adverse health effects, such as diabetes, in humans. The small intestinal epithelial cells are the main site of absorption of ingested arsenic, but they are not well characterized for arsenic exposure-related changes. This study identified gene expression changes in the small intestine that may be mechanistically linked to the adverse effects of arsenic exposure and possible interactions between arsenic ingestion and the pharmacokinetics of epoxide-containing drugs in vivo.

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来源期刊
CiteScore
6.50
自引率
12.80%
发文量
128
审稿时长
3 months
期刊介绍: An important reference for all pharmacology and toxicology departments, DMD is also a valuable resource for medicinal chemists involved in drug design and biochemists with an interest in drug metabolism, expression of drug metabolizing enzymes, and regulation of drug metabolizing enzyme gene expression. Articles provide experimental results from in vitro and in vivo systems that bring you significant and original information on metabolism and disposition of endogenous and exogenous compounds, including pharmacologic agents and environmental chemicals.
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