ARACHIDONATE PRODUCTS IN DIOXIN AND PCB TOXICITY

我们建议检查花生四烯酸代谢的异常，这可能 由二恶英和其他多卤代芳香烃(PAH)引起 以及花生四烯酸代谢产物在多环芳烃毒性中的作用。我们会 检测多环芳烃对前列腺素、白三烯合成的影响 和其他来自内源花生四烯酸和来自 外源性~(14)C标记花生四烯酸在多环芳烃潜在靶器官中的作用 毒性。前列腺素的测定采用放射免疫法、薄层扫描法和脂氧合酶法 产品经生物测定、薄层层析、高效液相色谱检测。多环芳烃对细胞色素P-450的影响 以及经典的(非P-450介导的)途径。 花生四烯酸代谢将使用选择性培养法进行检测 条件和化验程序。我们将确定是否会更改 多环芳烃对花生四烯酸的代谢与AH的激活有关 通过比较P-448型诱导剂和多环芳烃对受体的影响 非侵袭者对花生四烯酸代谢的影响 多环芳烃对花生四烯酸代谢影响的剂量-反应关系 P-488介导的肝脏和肝脏混合功能氧化酶的诱导 多环芳烃毒性的潜在靶器官。我们将研究是否 花生四烯酸产物可能参与诱发有毒物质 环氧合酶和环氧合酶对PAH的影响 脂氧合酶抑制剂和混合功能的氧化酶抑制剂和 多环芳烃的诱导剂(如果我们发现它们改变了花生四烯酸的代谢) 心脏毒性，表现为收缩反应减弱 去甲肾上腺素和全身性毒性 死亡率、水肿和胸腺退缩发生率增加。我们会的 也要研究在体外是否可以引起心脏毒性反应。 通过多环芳烃增加产量的花生四烯酸代谢产物 花生四烯酸抑制剂卵内暴露及体外减毒作用 新陈代谢。

We propose to examine abnormalities in arachidonic acid metabolism that may be caused by dioxin and other polyhalogenated aromatic hydrocarbons (PAH) and the role of arachidonic acid metabolites in PAH toxicity. We will examine the effects of PAH on the synthesis of prostaglandins, leukotrienes and other lipoxygenase products from endogenous arachidonic acid and from exogenous (14C) labelled arachidonic acid in potential target organs of PAH toxicity. Prostaglandins will be assayed by RIA and TLC and lipoxygenase products by bioassay, TLC and HPLC. PAH effects on cytochrome P-450 mediated as well as on classical (non-P-450 mediated) pathways of arachidonic acid metabolism will be examined using selective incubation conditions and assay procedures. We will determine whether changes in arachidonic acid metabolism by PAH are associated with activation of the Ah receptor by comparing the effects of PAH which are P-448 type inducers and noninudcers on arachidonic acid metabolism and by comparing the does-response relationships for PAH effects on arachidonic acid metabolism and on P-488 mediated mixed function oxidase induction in liver and in potential target organs of PAH toxicity. We will examine whether arachidonic acid products may participate in eliciting the toxic manifestations of PAH by examining the effect of cyclooxygenase and lipoxygenase inhibitors and of mixed function oxidase inhibitors and inducers (if we find that they alter arachidonic acid metabolism) on PAH cardiotoxicity as evidenced by a decreased contractile response to norepinephrine, and generalized toxicity as evidenced by increased mortality, increased incidence of edema and thymic involution. we will also investigate whether the cardiotoxic response can be elicited in vitro by those arachidonic acid metabolites whose production is increased by PAH exposure in ovo and attenuated in vitro by inhibitors of arachidonic acid metabolism.