Arachidonic acid metabolism by dioxin-induced cytochrome P-450: a new hypothesis on the role of P-450 in dioxin toxicity.
Arachidonic acid metabolism by dioxin-induced cytochrome P-450: a new hypothesis on the role of P-450 in dioxin toxicity.
复制标题
二恶英诱导的细胞色素 P-450 的花生四烯酸代谢：P-450 在二恶英毒性中作用的新假设。
DOI：
10.1016/0006-291x(90)91573-b
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发表时间：
1990
影响因子：
3.1
通讯作者：
Gross,SS
中科院分区：
文献类型：
--
作者：
Rifkind,AB;Gannon,M;Gross,SS
二恶英(2，3，7，8-四氯二苯并-对二恶英，TCDD)是一种高效的细胞色素P-450诱导剂。诱导的P-450在TCDD毒性中的作用一直不清楚，因为P-450既不能解毒TCDD，也不能激活它产生遗传毒性或细胞毒性的代谢物。我们使用鸡胚模型表明，TCDD导致NADPH依赖的花生四烯酸(AA)代谢显著增加，花生四烯酸(AA)是一种主要的细胞膜脂肪酸，它以极高的效力(ED50，6.3pmol/蛋)实现这一代谢，并且这种代谢是由TCDD诱导的细胞色素P-450催化的。因此，TCDD处理使P-450介导的AA肝微体代谢增加了六到十倍，以合成环氧化物和单羟基二十碳四烯酸，这些产物的不同生物学活性表明TCDD的毒性作用有关。相比之下，对照组只有x和x-1羟基AA的非活性产物显著形成。这些发现为P-450的诱导如何与TCDD的不同毒性效应相关开辟了新的视角。它们导致了一种新的假设，即TCDD诱导的细胞色素P-450将内源脂肪酸代谢成反应产物，进而介导或调节TCDD毒性的各种表现。
Dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD) is a highly potent inducer of cytochrome P-450. The role of the induced P-450 in TCDD toxicity has been obscure as P-450 neither detoxifies TCDD nor activates it to genotoxic or cytoxic metabolites. We show, using a chick embryo model, that TCDD causes major increases in the NADPH dependent metabolism of arachidonic acid (AA), a predominant cell membrane fatty acid, that it does so with extremely high potency (ED50, 6.3 pmol per egg) and that this metabolism is catalyzed by TCDD-induced cytochrome P-450 species. Thus, TCDD treatment increased by six to ten fold the P-450 mediated hepatic microsomal metabolism of AA to epoxides and monohydroxyeicosatetraenoic acids, products whose diverse biological activities suggest links to TCDD's toxic effects. In contrast, only x and x-1 hydroxy AA, inactive products, were significantly formed by the controls. These findings open a new perspective on how P-450 induction could be related to the diverse toxic effects of TCDD. They lead to the novel hypothesis that TCDD-induced cytochrome P-450 metabolizes an endogenous fatty acid to reactive products that in turn mediate or modulate varied manifestations of TCDD toxicity.