Mechanistic aspects of dioxin action.
Mechanistic aspects of dioxin action.
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DOI：
10.1021/tx00036a003
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发表时间：
1993-11
影响因子：
4.1
通讯作者：
J. Whitlock
中科院分区：
文献类型：
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作者：
J. Whitlock
2，3，7，8-四氯二苯并对二恶英(TCDD，Dioxin)*1**是一类卤代芳香烃的原型，它们产生相似的毒性模式，并似乎具有共同的作用机制，尽管它们的效力不同(1，2)。因为它是最有效的，TCDD比其他结构相关的化合物得到了更广泛的研究(图1)。TCDD在20世纪70年代臭名昭著，当时它被发现是除草剂橙剂中的污染物，并被证明会导致啮齿动物的出生缺陷。随后，二恶英因其广泛的分布、作为一种环境污染物的持久性、在食物链中的积累和毒性而继续引起人们的关注。在动物中，TCDD引起广泛的生物学效应，包括代谢途径的改变、免疫学变化、致畸效应和肿瘤(1，2)。TCDD的影响因动物物种不同而不同，这种情况使评估二恶英对人类健康的潜在危害的努力复杂化。在人类身上，二恶英会导致被称为氯痤疮的皮肤疾病；它还可能导致癌症和出生缺陷，这是公共卫生特别关注的问题。许多人接触了TCDD，主要是通过饮食来源，尽管也发生了职业性和意外接触。TCDD不是解毒系统的不良底物，例如微粒体细胞色素P450酶，它在代谢过程中将其他亲脂化合物氧化成不活跃的衍生物。由于其对新陈代谢的相对抵抗力，TCDD倾向于在体内持续存在，其在人类体内的半衰期约为10年(3)。因此，随着时间的推移，二恶英往往会在人体组织中积累，这引发了人们的担忧，即反复接触二恶英，即使浓度很低，也可能会引起不利的健康影响。流行病学研究还没有对二恶英对人类造成的健康风险做出明确的估计(4)，人们希望对二恶英作用机制的了解可能会在这个问题上带来额外的启发(5)。机理研究可以揭示导致二恶英不良影响的生物化学途径和生物事件类型。例如，TCDD通过细胞内蛋白质(ah受体)起作用，这是一种配体依赖的转录因子，与第二种蛋白质(称为Arnt)一起发挥作用；因此，从机械论的角度来看，TCDD的不利影响似乎反映了基因表达的持续变化。机制研究还表明，几种蛋白质参与了TCDD的基因调控效应，对TCDD的反应可能涉及到多种遗传和环境因素之间相对复杂的相互作用。这种机械性的信息强加给
2, 3, 7, 8-Tetrachlorodibenzo-p-dioxin (TCDD, dioxin)* 1** is the prototype for a class of halogenated aromatic hydro-carbons, which produce similar patterns oftoxicity and appear to have a common mechanism of action, though they differ in potency (1, 2). Because it is the most potent, TCDD has been studied much more extensively than other, structurally-related compounds (Figure 1). TCDD achieved notoriety in the 1970s, when it was discovered to be a contaminant in the herbicide Agent Orange and was shown to produce birth defects in rodents. Subse-quently, dioxin has continued to generate concern because of its widespread distribution, its persistence as an environmental contaminant, its accumulation within the food chain, and its toxic potency. In animals, TCDD elicits a wide range of biological effects, including alterations in metabolic pathways, immunological changes, teratogenic effects, and neoplasia (1, 2). TCDD’s effects differ among animal species, a situation that complicates attempts to assess dioxin’s potential hazard to human health. In humans, the dioxin can produce the skin condition known as chloracne; the possibility that it also produces cancer and birth defects is of particular public health concern. Many individuals have been exposed toTCDD, primarily from dietary sources, although occupational and accidental exposures have also occurred. TCDD is a poor substrate for detoxification systems, such as the microsomal cytochrome P450 enzymes, which oxygenate other lipophilic compounds during their metabolic processing to inactive derivatives. Because of its relative resistance to metabolism, TCDD tends to persist in the body, and its half-life in humans is of the order of 10 years (3). Therefore, dioxin tends to accumulate in human tissues over time, raising the concern that repeated exposures, even to “low” concentrations, may evoke adverse health effects. Epidemiological studies have not produced a well-defined estimate of the health risk that dioxin poses to humans (4), and there has been hope that knowledge of the mechanism of dioxin actionmay shed additionallight on this issue (5). Mechanistic studies can reveal the bio-chemical pathways and types of biological events that contribute to dioxin’sadverse effects. For example, TCDD acts via an intracellular protein (the Ah receptor), which is a ligand-dependent transcription factor that functions in partnership with a second protein (known as Arnt); therefore, from a mechanistic standpoint, TCDD’s adverse effects appear likely to reflect sustained alterations in gene expression. Mechanistic studies also indicate that several proteins contribute to TCDD’s gene regulatory effects and that the response toTCDD probably involves a relatively complex interplay between multiple genetic and environmental factors. Such mechanistic information imposes