Poland A, Kende A
Fed Proc. 1976 Oct;35(12):2404-11.
The chlorinated dibenzo-p-dioxins and dibenzofurans are formed as trace contaminants during the synthesis of a number of commercially important chemicals. The prototype compound of this group, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), is one of the most potent low molecular weight toxins and teratogens known, and its inadvertent dispersion in the environment has caused concern about the potential hazard to human health. In studying the biochemical effects of TCDD, it was found to be extraordinarily potent as an inducer of two hepatic enzymes: 1) delta-aminolevulinic acid synthetase, the initial and rate-limiting enzyme in heme synthesis, and 2) aryl hydrocarbon hydroxylase, a cytochrome P-450-mediated microsomal monooxygenase. Among a series of halogenated dibenzo-p-dioxins there is an excellent correlation between their toxic potency and their potency as inducers of these two enzymes. The administration of polycyclic aromatic hydrocarbons (e.g., 3-methylcholanthrene (MC)) to certain inbred strains of mice induces aryl hydrocarbon hydroxylase, while other inbred strains fail to respond; and the trait of aryl hydrocarbon responsiveness is inherited as an autosomal dominant. TCDD, about 30,000 times as potent as MC, induces all strains whether responsive or nonresponsive to MC; however, the responsive strains are more sensitive (ED 50 approximately 1 X 10(-9) mole/kg) to TCDD than are the nonresponsive strains (ED50 larger than or equal to 1 X 10(-8) mole/kg). The results suggest that the mutation in the nonresponsive strains results in a ligand binding site (an induction receptor) that has a diminished affinity for MC and TCDD. The correlation among the halogenated dibenzo-p-dioxins, between their potency as toxins and their potency as inducers of aryl hydrocarbon hydroxylase, is discussed in relationship to various proposed mechanisms of toxicity.
在许多重要商业化学品的合成过程中，会形成氯化二苯并 - p - 二恶英和二苯并呋喃这类微量污染物。该类化合物的原型2,3,7,8 - 四氯二苯并 - p - 二恶英（TCDD），是已知的最具毒性的低分子量毒素和致畸剂之一，其在环境中的意外扩散引发了人们对人类健康潜在危害的担忧。在研究TCDD的生化效应时，发现它作为两种肝酶的诱导剂具有极强的作用：1）δ - 氨基乙酰丙酸合成酶，血红素合成中的起始和限速酶；2）芳烃羟化酶，一种细胞色素P - 450介导的微粒体单加氧酶。在一系列卤代二苯并 - p - 二恶英中，它们的毒性效力与其作为这两种酶诱导剂的效力之间存在极好的相关性。给某些近交系小鼠施用多环芳烃（如3 - 甲基胆蒽（MC））可诱导芳烃羟化酶，而其他近交系则无反应；芳烃反应性这一特性作为常染色体显性遗传。TCDD的效力约为MC的30,000倍，无论对MC有反应还是无反应的品系，它都能诱导；然而，有反应的品系对TCDD比无反应的品系更敏感（半数有效剂量约为1×10⁻⁹摩尔/千克）（无反应品系的半数有效剂量大于或等于1×10⁻⁸摩尔/千克）。结果表明，无反应品系中的突变导致配体结合位点（诱导受体）对MC和TCDD的亲和力降低。本文结合各种提出的毒性机制，讨论了卤代二苯并 - p - 二恶英在其作为毒素的效力与作为芳烃羟化酶诱导剂的效力之间的相关性。
