ARACHIDONATE PRODUCTS IN DIOXIN AND PCB TOXICITY

我们建议检查花生四烯酸代谢异常， 二恶英和其他多卤代芳烃（PAH） 以及花生四烯酸代谢物在多环芳烃毒性中的作用。 我们将 检测PAH对白藜芦醇、白三烯合成的影响， 和来自内源性花生四烯酸的其它脂氧合酶产物以及来自 PAH潜在靶器官中的外源性（14 C）标记花生四烯酸 毒性 将通过RIA和TLC以及脂氧合酶测定前列腺素 产品通过生物测定，TLC和HPLC。 PAH对细胞色素P-450的影响 介导的以及经典的（非P-450介导的） 将使用选择性孵育来检查花生四烯酸代谢 条件和测定程序。 我们将决定是否改变 PAH代谢花生四烯酸与AH的激活有关 通过比较P-448型诱导剂PAH和 非抑制剂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-效应关系 以及P-488介导的肝脏和肝脏中的混合功能氧化酶诱导作用。 PAH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毒性 通过检查环氧合酶的作用， 脂氧合酶抑制剂和混合功能氧化酶抑制剂， 诱导剂（如果我们发现它们改变花生四烯酸代谢） 心脏毒性，表现为对 去甲肾上腺素和全身毒性，表现为 死亡率、水肿和胸腺退化发生率增加。 我们将 还研究了是否可以在体外引起心脏毒性反应 通过那些花生四烯酸代谢产物，其生产增加PAH 卵内暴露并通过花生四烯酸抑制剂在体外减弱 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.