文摘
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 (iAsV), arsenite (iAsIII), monomethylarsonic acid (MMAV), monomethylmonothioarsonic acid (MMMTAV), dimethylarsinic acid (DMAV), dimethylarsinous acid (DMAIII), dimethylmonothioarsinic acid, (DMMTAV), and dimethyldithioarsinic acid (DMDTAV) in human bladder cancer EJ-1 cells. The order of cytotoxicity of these arsenic compounds in EJ-1 human bladder cancer cells was DMAIII, DMMTAV > iAsIII iAsV > MMMTAV > MMAV, DMAV, and DMDTAV, indicating that the sulfur-containing DMMTAV was among the most toxic arsenic compounds similar to trivalent DMAIII. 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 iAsIII, DMAIII, and DMMTAV. Cellular exposure to DMMTAV resulted in reduced protein expression of p53 and p21, increased DNA damage, and increased intracellular hROS (hydroxyl radical). In contrast, iAsIII significantly increased the protein expression of p21 and p53 and did not increase the hROS at the IC50. Intracellular glutathione (GSH) was reduced by 60% after exposure to DMAIII or DMMTAV, suggesting that DMMTAV causes cell death through oxidative stress. In contrast, GSH levels increased in cells exposed to iAsIII, and hROS only increased after a long exposure to iAsIII. Our findings demonstrate that DMMTAV may be one of the most toxicologically potent arsenic species, relevant to arsenic-induced carcinogenicity in the urinary bladder.