Comparative Toxicity of Arsenic Metabolites in Human Bladder Cancer EJ-1 Cells
Comparative Toxicity of Arsenic Metabolites in Human Bladder Cancer EJ-1 Cells
复制标题
人膀胱癌 EJ-1 细胞中砷代谢物的比较毒性
DOI：
10.1021/tx200291p
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发表时间：
2011-09-01
影响因子：
4.1
通讯作者：
Le, X. Chris
中科院分区：
文献类型：
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作者：
Naranmandura, Hua;Carew, Michael W.;Le, X. Chris
人类膀胱是砷致癌作用的主要靶器官之一，尿中砷代谢产物被怀疑直接参与了砷的致癌作用。硫代砷通常存在于人类和动物的尿液中，也被认为是高毒性的砷代谢物。本研究旨在深入了解尿中发现的砷物种的毒性和蓄积，包括砷酸盐（iAs（V）），亚砷酸盐（iAs（III）），单甲基胂酸（MMA（V）），单甲基硫代胂酸（MMMTA（V）），二甲基胂酸（DMA（V）），二甲基亚胂酸（DMA（III）），二甲基硫代胂酸（DMMTA（V）），和二甲基二硫代胂酸（DMDTA（V））。这些砷化合物对EJ-1人膀胱癌细胞的毒性顺序为DMA（III）、DMMTA（V）> iAs（III）> iAs（V）> MMMTA（V）> MMA（V）、DMA（V）和DMDTA（V），表明含硫的DMMTA（V）是毒性最大的砷化合物之一，与三价DMA（III）相似。我们进一步表征了iAs（III）、DMA（III）和DMMTA（V）暴露后细胞中DNA损伤、高活性氧（hROS）的产生以及蛋白质p21和p53的表达。细胞暴露于DMMTA（V）导致p53和p21蛋白表达降低，DNA损伤增加，细胞内hROS（羟基自由基）增加。相反，iAs（III）显著增加了p21和p53的蛋白表达，但没有增加IC（50）处的hROS。细胞内谷胱甘肽（GSH）在暴露于DMA（III）或DMMTA（V）后减少了60%，表明DMMTA（V）通过氧化应激导致细胞死亡。相反，GSH水平在暴露于iAs（III）的细胞中增加，hROS仅在长时间暴露于iAs（III）后增加。我们的研究结果表明，DMMTA（V）可能是最强的毒理学砷物种之一，有关砷诱导的膀胱致癌性。
The human bladder is one of the primary target organs for arsenic-induced carcinogenicity, and arsenic metabolites in urine have been suspected to be directly involved in carcinogenesis. Thioarsenicals are commonly found in human and animal urine and are also considered to be highly toxic arsenic metabolites. The present study was performed to gain insight into the toxicity and accumulation of arsenic species found in urine, including arsenate (iAs(V)), arsenite (iAs(III)), monomethylarsonic acid (MMA(V)), monomethylmonothioarsonic acid (MMMTA(V)), dimethylarsinic acid (DMA(V)), dimethylarsinous acid (DMA(III)), dimethylmonothioarsinic acid, (DMMTA(V)), and dimethyldithioarsinic acid (DMDTA(V)) in human bladder cancer EJ-1 cells. The order of cytotoxicity of these arsenic compounds in EJ-1 human bladder cancer cells was DMA(III), DMMTA(V) > iAs(III) >> iAs(V) > MMMTA(V) > MMA(V), DMA(V), and DMDTA(V), indicating that the sulfur-containing DMMTA(V) was among the most toxic arsenic compounds similar to trivalent DMA(III). We further characterized the DNA damage, generation of highly reactive oxygen species (hROS), and expression of proteins p21 and p53 in cells after exposure to iAs(III), DMA(III), and DMMTA(V). Cellular exposure to DMMTA(V) resulted in reduced protein expression of p53 and p21, increased DNA damage, and increased intracellular hROS (hydroxyl radical). In contrast, iAs(III) significantly increased the protein expression of p21 and p53 and did not increase the hROS at the IC(50). Intracellular glutathione (GSH) was reduced by 60% after exposure to DMA(III) or DMMTA(V), suggesting that DMMTA(V) causes cell death through oxidative stress. In contrast, GSH levels increased in cells exposed to iAs(III), and hROS only increased after a long exposure to iAs(III). Our findings demonstrate that DMMTA(V) may be one of the most toxicologically potent arsenic species, relevant to arsenic-induced carcinogenicity in the urinary bladder.