Toxicity of Dimethylmonothioarsinic Acid toward Human Epidermoid Carcinoma A431 Cells

• Published in: Chemical research in toxicology Vol. 20; no. 8; pp. 1120 - 1125
• Main Authors: Naranmandura, Hua, Ibata, Kenji, Suzuki, Kazuo T
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 01.08.2007
• Subjects: Arsenic; Arsenic Poisoning; Arsenicals - adverse effects; Arsenicals - metabolism; bladder; Cacodylic Acid - analogs & derivatives; Cacodylic Acid - metabolism; Cacodylic Acid - toxicity; cell cycle; Cell Cycle - drug effects; Cell Cycle - physiology; Cell Division; Cell Line, Tumor; Cell Survival - drug effects; Cell Survival - physiology; dimethylarsinic acid; dimethyldithioarsinic acid; dimethylmonothioarsinic acid; G1 Phase; Humans; Lethal Dose 50; Oxidation-Reduction; reactive oxygen species; Reactive Oxygen Species - metabolism; S Phase; skin; Skin Neoplasms - chemically induced; Skin Neoplasms - pathology; thioarsenical; Time Factors; dimethyldithioarsinic acid; dimethylmonothioarsinic acid; Arsenic; cell cycle; bladder; reactive oxygen species; dimethylarsinic acid; skin; thioarsenical
• ISSN: 0893-228X; 1520-5010
• DOI: 10.1021/tx700103y

Chronic ingestion of arsenic-contaminated drinking water induces skin lesions and urinary bladder cancer in humans. It is now recognized that thioarsenicals such as dimethylmonothioarsinic acid (DMMTAV) are commonly excreted in the urine of humans and animals and that the production of DMMTAV may be a risk factor for the development of the diseases caused by arsenic. The toxicity of DMMTAV was compared with that of related nonthiolated arsenicals with respect to cell viability, uptake ability, generation of reactive oxygen species (ROS), and cell cycle progression of human epidermoid carcinoma A431 cells, arsenate (iAsV), arsenite (iAsIII), dimethylarsinic acid (DMAV), and dimethylarsinous acid (DMAIII) being used as reference nonthiolated arsenicals. DMMTAV (LC50 = 10.7 µM) was shown to be much more cytotoxic than iAsV (LC50 = 571 µM) and DMAV (LC50 = 843 µM), and its potency was shown to be close to that of trivalent arsenicals iAsIII (LC50 = 5.49 µM) and DMAIII (LC50 = 2.16 µM). The greater cytotoxicity of DMMTAV was associated with greater cellular uptake and distribution, and the level of intracellular ROS remarkably increased in A431 cells upon exposure to DMMTAV compared to that after exposure to other trivalent arsenicals at the respective LC50. Exposure of DMMTAV to cells for 24 h induced cell cycle perturbation. Namely, the percentage of cells residing in S and G2/M phases increased from 10.2 and 15.6% to 46.5 and 20.8%, respectively. These results suggest that although DMMTAV is a pentavalent arsenical, it is taken up efficiently by cells and causes various levels of toxicity, in a manner different from that of nonthiolated pentavalent arsenicals, demonstrating that DMMTAV is one of the most toxic arsenic metabolites. The high cytotoxicity of DMMTAV was explained and/or proposed by (1) efficient uptake by cells followed by (2) its transformation to DMAV, (3) producing ROS in the redox equilibrium between DMAV and DMAIII in the presence of glutathione.