Arsenic co-exposure potentiates benzo[a]pyrene genotoxicity
Arsenic co-exposure potentiates benzo[a]pyrene genotoxicity
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DOI：
10.1016/s1383-5718(02)00057-8
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发表时间：
2002-05-27
影响因子：
1.9
通讯作者：
Puga, A
中科院分区：
文献类型：
--
作者：
Maier, A;Schumann, BL;Puga, A
环境中同时暴露于砷和多环芳烃（例如苯并[a]芘（BaP））的复杂混合物很常见。这两种环境污染物具有致癌性，但它们在诱发癌症中分子相互作用的性质尚不清楚。已提出加性或协同相互作用来解释为什么砷本身不是一种有效的诱变剂，但它与多种 DNA 损伤剂具有共同诱变作用。我们研究了 BaP-砷混合物的遗传毒性。我们发现，将小鼠肝癌 Hepa-I 细胞暴露于低浓度的亚砷酸盐会使 BaP-DNA 加合物水平增加多达 18 倍。这种效应需要细胞色素 p450 1A1 (CYP1A1) 激活 BaP，尽管亚砷酸盐不会改变 BaP 诱导的 CYP1A1 酶活性，这表明亚砷酸盐在代谢 BaP 激活的下游发挥作用。谷胱甘肽稳态对于调节亚砷酸盐的效力很重要。在还原型谷胱甘肽耗尽的细胞中，亚砷酸盐比在对照培养基中用 BaP 和亚砷酸盐共同处理的细胞更大程度地增加了 BaP-DNA 加合物的形成。尽管砷的致突变性归因于对 DNA 修复的抑制，但亚砷酸盐处理并没有改变 BaP 处理细胞中的加合物去除动力学，这表明 DNA 修复的上游机制是导致加合物水平增加的原因。亚砷酸盐和 BaP 的浓度单独使用时没有可测量的诱变作用，当组合使用时，Hprt 位点的突变频率增加了八倍，这表明 BaP 和亚砷酸盐之间存在诱变反应。这些结果为流行病学研究中观察到的砷与多环芳烃诱发的癌症之间的积极相互作用提供了强有力的支持，并有助于确定可能与砷突变有关的其他机制步骤。 (C) 2002 Elsevier Science B.V. 保留所有权利。
Co-exposures to complex mixtures of arsenic and polycyclic aromatic hydrocarbons such as benzo[a]pyrene (BaP) are common in the environment, These two environmental pollutants are carcinogenic, but the nature of their molecular interactions in the induction of cancer is not well understood. Additive or synergistic interactions have been proposed to explain why arsenic, which is not a potent mutagen itself, is comutagenic with a variety of DNA-damaging agents. We have examined the genotoxicity of BaP-arsenic mixtures. We find that exposure of mouse hepatoma Hepa-I cells to low concentrations of arsenite increases BaP-DNA adduct levels by as much as 18-fold. This effect requires the activation of BaP by cytochrome p450 1A1 (CYP1A1), although arsenite does not alter BaP-inducible CYP1A1 enzymatic activity, suggesting that arsenite acts downstream of metabolic BaP activation. Glutathione homeostasis was important in modulating the potency of arsenite. In cells depleted of reduced glutathione, arsenite increased BaP-DNA adduct formation by an even greater degree than in cells co-treated with BaP and arsenite in control medium. Although arsenic comutagenicity has been attributed to inhibition of DNA repair, arsenite treatment did not alter adduct removal kinetics in BaP-treated cells, suggesting that mechanisms upstream of DNA repair are responsible for increased adduct levels. Concentrations of arsenite and BaP that had no measurable mutagenic effect alone, increased mutation frequency at the Hprt locus by eight-fold when given in combination, demonstrating a comutagenic response between BaP and arsenite. These results provide strong support for the positive interaction between arsenic and PAH-induced cancer observed in epidemiology studies, and help to identify additional mechanistic steps likely to be involved in arsenic comutagenesis. (C) 2002 Elsevier Science B.V. All rights reserved.