Hydroperoxy-10,12-octadecadienoic acid stimulates cytochrome P450 3A protein aggregation by a mechanism that is inhibited by substrate.
Hydroperoxy-10,12-octadecadienoic acid stimulates cytochrome P450 3A protein aggregation by a mechanism that is inhibited by substrate.
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Hydroperoxy-10,12-十八碳二烯酸通过底物抑制的机制刺激细胞色素 P450 3A 蛋白聚集。
DOI：
10.1021/bi0349975
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发表时间：
2003
期刊：
影响因子：
--
通讯作者：
Zangar,RichardC
中科院分区：
文献类型：
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作者：
Kimzey,AmyL;Weitz,KarlK;Guengerich,FPeter;Zangar,RichardC
我们最近证明，尼卡地平处理的大鼠的微粒体在 37 °C 下孵育时会形成细胞色素 P450 3A (CYP3A) 聚集体。 CYP3A 底物抑制蛋白质聚集和随后的降解，表明该过程对于底物介导的 CYP3A 稳定很重要。在本文中，我们证明氧化应激是在培养的微粒体和纯化酶重建系统中形成 CYP3A 聚集体的关键因素。我们的数据进一步表明，氧化应激的影响是由脂质氢过氧化物介导的，而脂质氢过氧化物可通过 CYP3A 有效代谢。在存在底物的情况下，CYP3A 介导的脂质过氧化氢代谢以及相关的蛋白质聚集受到抑制。因此，这些研究提供了为什么 CYP3A 的半衰期相对较短以及底物如何稳定 CYP3A 的机制模型。
We recently demonstrated that microsomes from nicardipine-treated rats will form cytochrome P450 3A (CYP3A) aggregates when incubated at 37 °C. CYP3A substrates inhibited the protein aggregation and subsequent degradation, suggesting that this process is important in substrate-mediated stabilization of CYP3A. In this paper, we demonstrate that oxidative stress is a key factor in the formation of CYP3A aggregates in incubated microsomes and in a reconstituted system with purified enzymes. Our data further suggest that the effects of oxidative stress are mediated by lipid hydroperoxides, which are efficiently metabolized by CYP3A. In the presence of substrate, the CYP3A-mediated lipid hydroperoxide metabolism is inhibited along with the associated protein aggregation. Therefore, these studies provide a mechanistic model of why CYP3A has a relatively short half-life and how substrates stabilize CYP3A.