环境中的持久性自由基会刺激 CYP2E1 介导的活性氧生成,从而影响底物代谢。

IF 4.4 3区 医学 Q1 PHARMACOLOGY & PHARMACY
George F Cawley, J Patrick Connick, Marilyn K Eyer, Wayne L Backes
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引用次数: 0

摘要

环境持久性自由基(EPFRs)是最近公认的颗粒物成分,可导致呼吸道和心血管中毒。EPFR 的毒性机制似乎与它们产生活性氧(ROS)、造成氧化损伤的能力有关。研究表明,EPFR 会影响 P450 的功能,通过 Ah 受体诱导某些形式的 P450 表达。然而,EPFRs 的另一个特点是能够抑制 P450 的活性。CYP2E1 是受到 EPFR(MCP230)抑制的 P450 之一。众所周知,CYP2E1 也会产生 ROS,因此了解 EPFR 影响该酶功能的能力并确定其中的机制非常重要。研究表明,CYP2E1 会受到 EPFR 的抑制,其次是非 EPFR 颗粒。由于 EPFR 介导的抑制作用在 NADPH-细胞色素 P450 还原酶(POR)浓度过饱和时更为强烈,因此对 POR-CYP2E1 复合物的形成和电子传递的破坏进行了研究。令人惊讶的是,EPFRs 既没有抑制 POR 和 CYP2E1 之间的复合物形成,也没有抑制它们之间的电子传递。对 ROS 产生情况的研究表明,MCP230 产生的 ROS 量高于非 EPFR 的 CuO-Si。当在污染物-粒子系统中加入含有 POR/CYP2E1 的重组系统时,ROS 的产生会受到协同刺激。结果表明,EPFR 会抑制 CYP2E1 介导的底物代谢,但不会改变电子传递,反而会刺激 ROS 的产生。综合来看,这些结果与 EPFR 通过抑制底物代谢和增加 ROS 生成来影响 CYP2E1 功能的观点一致。意义声明 环境持久性自由基通过抑制单氧化酶的活性来影响 CYP2E1 的功能。这种抑制不是由于 POR-CYP2E1 复合物的破坏或电子传递的抑制,而是由于 NADPH 和氧消耗从底物代谢到 ROS 生成的脱钩。这些结果表明,EPFR 阻断了外来化合物的代谢,同时也协同刺激了活性氧的形成,从而导致生物体内的氧化损伤。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Environmentally Persistent Free Radicals stimulate CYP2E1-mediated generation of reactive oxygen species at the expense of substrate metabolism.

Environmentally persistent free radicals (EPFRs) are a recently recognized component of particulate matter that cause respiratory and cardiovascular toxicity. The mechanism of EPFR toxicity appears to be related to their ability to generate reactive oxygen species (ROS), causing oxidative damage. EPFRs were shown to affect P450 function, inducing the expression of some forms through the Ah receptor. However, another characteristic of EPFRs lies in their ability to inhibit P450 activities. CYP2E1 is one of the P450s that is inhibited by EPFR (MCP230) exposure. As CYP2E1 is also known to generate ROS, it is important to understand the ability of EPFRs to influence the function of this enzyme and to identify the mechanisms involved. CYP2E1 was shown to be inhibited by EPFRs, and to a lesser extent by non-EPFR particles. As EPFR-mediated inhibition was more robust at subsaturating NADPH-cytochrome P450 reductase (POR) concentrations, disruption of POR·CYP2E1 complex formation and electron transfer were examined. Surprisingly, neither complex formation nor electron transfer between POR and CYP2E1 were inhibited by EPFRs. Examination of ROS production showed that MCP230 generated a greater amount of ROS than the non-EPFR CuO-Si. When a POR/CYP2E1-containing reconstituted system was added to the pollutant-particle systems there was a synergistic stimulation of ROS production. The results indicate that EPFRs cause inhibition of CYP2E1-mediated substrate metabolism, yet do not alter electron transfer and actually stimulate ROS generation. Taken together, the results are consistent with EPFRs affecting CYP2E1 function by inhibiting substrate metabolism and increasing the generation of ROS. Significance Statement Environmentally persistent free radicals affect CYP2E1 function by inhibition of monooxygenase activity. This inhibition is not due to disruption of the POR·CYP2E1 complex or inhibition of electron transfer, but due to uncoupling of NADPH and oxygen consumption from substrate metabolism to the generation of ROS. These results show that EPFRs block the metabolism of foreign compounds, and also synergistically stimulate the formation of reactive oxygen species that lead to oxidative damage within the organism.

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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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