Role of the aromatic hydrocarbon receptor and [Ah] gene battery in the oxidative stress response, cell cycle control, and apoptosis
Role of the aromatic hydrocarbon receptor and [Ah] gene battery in the oxidative stress response, cell cycle control, and apoptosis
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DOI：
10.1016/s0006-2952(99)00310-x
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发表时间：
2000-01-01
影响因子：
5.8
通讯作者：
Dalton, TP
中科院分区：
文献类型：
--
作者：
Nebert, DW;Roe, AL;Dalton, TP
综述了芳烃电池表征的历史和发展。该电池代表了Ah受体（AHR）介导的控制至少有六个，可能更多，二恶英诱导基因;两个细胞色素P450基因-P450 1A 1和1A 2（Cyp 1a 1，Cyp 1a 2）-和四个非P450基因，已被实验证明是该电池的成员。内源性和外源性底物的代谢可能是每一种P450酶，但肯定是CYP 1A 1和CYP 1A 2（部分位于线粒体中），已被证明会引起反应性含氧代谢物（ROM）介导的氧化应激。氧化应激通过亲电反应元件（EPRE）DNA基序激活基因，而二恶英（急性）通过AHR介导的芳香烃反应元件（AHRE）DNA基序激活基因。与二恶英相反，容易代谢为ROM的AHR配体（例如苯并[a]芘、β-萘啶酮）通过AHRE和EPRE激活基因。AHR在细胞周期调控和凋亡中的重要性才刚刚开始被认识。目前的证据表明，CYP 1A 1和CYP 1A 2酶可能控制AHR的假定内源性配体的水平，但CYP 1A 1/1A 2代谢产生ROM介导的氧化应激，这可以通过[Ah]电池中的四个非P450 EPRE驱动的基因来改善。氧化应激是促使细胞凋亡的主要信号;然而，决定细胞在细胞凋亡和细胞周期继续之间的决定的精确机制或分子仍有待阐明。因此，AHR和[Ah]电池基因的总作用代表了凋亡级联中的关键上游事件，在促进和预防ROM介导的氧化应激之间提供了复杂的平衡。当然，AHR和[Ah]酶的这些提议的内源性功能是除了经常描述的各种外来化学物质的“代谢增强”和“解毒”功能之外的。生物化学制药59;1：65-85，2000. (C)1999 Elsevier Science Inc.
The chronology and history of characterizing the aromatic hydrocarbon [Ah] battery is reviewed. This battery represents the Ah receptor (AHR)-mediated control of at least six, and probably many more, dioxin-inducible genes; two cytochrome P450 genes-P450 1A1 and 1A2 (Cyp1a1, Cyp1a2)-and four non-P450 genes, have experimentally been documented to be members of this battery. Metabolism of endogenous and exogenous substrates by perhaps every P450 enzyme, but certainly CYP1A1 and CYP1A2 (which are located, in part, in the mitochondrion), have been shown to cause reactive oxygenated metabolite (ROM) mediated oxidative stress. Oxidative stress activates genes via the electrophile response element (EPRE) DNA motif, whereas dioxin (acutely) activates genes via the AHR-mediated aromatic hydrocarbon response clement (AHRE) DNA motif. In contrast to dioxin,,AHR ligands that are readily metabolized to ROMs (e.g. benzo[a]pyrene, beta-naphthoflavone) activate genes via both AHREs and the EPRE. The importance of the AHR in cell cycle regulation and apoptosis has just begun to be realized. Current evidence suggests that the CYP1A1 and CYP1A2 enzymes might control the level of the putative endogenous Ligand of the AHR, but that CYP1A1/1A2 metabolism generates ROM-mediated oxidative stress which can be ameliorated by the four non P450 EPRE-driven genes in the [Ah] battery. Oxidative stress is a major signal in precipitating apoptosis; however, the precise mechanism, or molecule, which determines the cell's decision between apoptosis and continuation with the cell cycle, remains to be elucidated. The total action of,AHR and the [Ah] battery genes therefore represents a pivotal upstream event in the apoptosis cascade, providing an intricate balance between promoting and preventing ROM-mediated oxidative stress. These proposed endogenous functions of the AHR and [Ah] enzymes are, of course, in addition to the frequently described functions of "metabolic potentiation" and "detoxification" of various foreign chemicals. BIOCHEM PHARMACOL 59;1:65-85, 2000. (C) 1999 Elsevier Science Inc.