Possible differences in the mechanism of malignant transformation of HaCaT cells by arsenite and its dimethyl metabolites, particularly dimethylthioarsenics

Background: : As a confirmed human carcinogen, arsenic can cause skin cancer, lung cancer, etc. However, its carcinogenic mechanism is still unclear. In recent years, the oxidative stress hypothesis has become widely accepted. In mammals it has been found that arsenic can be converted to dimethylarsinous acid (DMA(III)) and dimethylmonothioarsinic acid (DMMTA(V)) through a series of methylation and redox reactions. DMA(I)(II) and DMMTA(V) are highly toxic. Methods: : Human keratinocytes (HaCaT) were exposed to different concentrations of NaAsO2 (IAsIII), DMMTA(V) and DMA(III) for 24 h. Reactive oxygen species (hydrogen peroxide and superoxide), oxidative damage markers (8-hydroxydeoxyguanosine and malondialdehyde), and antioxidant markers (glutathione and superoxide dismutase) were measured. In addition, sulfane sulfurs were measured in HaCaT cells and a cell-free system. Results: : In the DMMTA(V) and DMA(III) treatment groups, the levels of hydrogen peroxide and superoxide in HaCaT cells were higher than in the IAsIII treatment groups at the same dose. Levels of 8 - OHdG and MDA in the DMMTA(V) and DMA(III) treatment groups were also higher than those in the IAs III treatment groups at the same dose. However, in the DMMTA v and DMA III treatment groups, the levels of GSH and SOD activity were lower than that in the IAs m treatment groups. In DMMTA(V)-treated HaCaT cells, sulfane sulfurs were produced. Further, it was found that DMMTA(V) could react with DMDTA(V) to form persulfide in the cell-free system, which may explain the mechanism of the formation of sulfane sulfurs in DMMTA(V)-treated HaCaT cells. Conclusions: : DMMTA(V) and DMA(III) more readily induce reactive oxygen species (ROS) and cause oxidative damage in HaCaT cells than inorganic arsenic. Further, the persulfide formed by the reaction of DMMTA(V) and DMDTA(V) produced from the metabolism of DMMTA(v) may induce a stronger reductive defense mechanism than GSH against the intracellular oxidative stress of DMMTA(V). However, the cells exposed to arsenite are transformed by the continuous nuclear translocation of Nrf2 due to oxidative stress, and the persulfide from dimethylthioarsenics may promote Nrf2 by the combination with thiol groups, especially redox control key protein, Keapl, eventually cause nuclear translocation of sustained Nrf2.