Molecular Toxicology Program, University of California, Los Angeles, California 90095, USA.
Toxicol Appl Pharmacol. 2012 Mar 1;259(2):143-51. doi: 10.1016/j.taap.2011.12.009. Epub 2011 Dec 20.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) adversely affects many mammalian organs and tissues. These effects are mediated by the aryl hydrocarbon receptor (AHR). CYP1A1, CYP1A2 and CYP1B1 are upregulated by the liganded AHR. These (and other) cytochromes P450 can metabolize arachidonic acid into a variety of bioactive eicosanoids. Towards investigating a potential role of eicosanoids in TCDD toxicity, arachidonic acid, two other unsaturated long-chain fatty acids, and up to twenty-five eicosanoids were measured in five organs/tissues of male and female wild-type and Ahr null mice treated or untreated with TCDD. TCDD generally increased the levels of the four dihydroxyeicosatrienoic acids (DHETs) and (where measured) 5,6-epoxyeicosatrienoic acid and 18-, 19- and 20-hydroxyeicosatrienoic acids (HETEs) in the serum, liver, spleen and lungs, but not the heart, of both sexes, and increased the levels in the serum, liver and spleen of several metabolites that are usually considered products of lipoxygenase activity, but which may also be generated by cytochromes P450. TCDD also increased the levels of the esterified forms of these eicosanoids in the liver in parallel with the corresponding free forms. The levels of prostanoids were generally not affected by TCDD. The above changes did not occur in Ahr null mice, and are therefore mediated by the AHR. TCDD increased the mRNA levels of Cyp1a1, Cyp1a2, Cyp1b1 and the Pla2g12a form of phospholipase A(2) to varying degrees in the different organs, and these increases correlated with some but not all the changes in eicosanoids levels in the organs, suggesting that other enzymes may also be involved.
2,3,7,8-四氯二苯并对二恶英（TCDD）对许多哺乳动物器官和组织都有不良影响。这些影响是由芳烃受体（AHR）介导的。CYP1A1、CYP1A2 和 CYP1B1 被配体 AHR 上调。这些（和其他）细胞色素 P450 可以将花生四烯酸代谢为多种生物活性类二十烷酸。为了研究类二十烷酸在 TCDD 毒性中的潜在作用，在雄性和雌性野生型和 Ahr 缺失小鼠的五个器官/组织中测量了花生四烯酸、两种其他不饱和长链脂肪酸和多达二十五种类二十烷酸，这些小鼠用或不用 TCDD 处理。TCDD 通常会增加血清、肝脏、脾脏和肺中四种二羟二十碳三烯酸（DHETs）和（如果有测量）5,6-环氧二十碳三烯酸以及 18-、19-和 20-羟二十碳三烯酸（HETEs）的水平，但心脏除外，在两性中，并增加了几种代谢物的水平，这些代谢物通常被认为是脂氧合酶活性的产物，但也可能由细胞色素 P450 生成。TCDD 还增加了肝脏中这些类二十烷酸酯化形式的水平，与相应的游离形式平行增加。前列腺素的水平通常不受 TCDD 影响。Ahr 缺失小鼠中未发生上述变化，因此这些变化是由 AHR 介导的。TCDD 不同程度地增加了不同器官中 Cyp1a1、Cyp1a2、Cyp1b1 和磷脂酶 A(2)的 Pla2g12a 形式的 mRNA 水平，这些增加与器官中某些但不是所有类二十烷酸水平的变化相关，表明其他酶也可能参与其中。
