Differences in apoptotic signaling and toxicity between dimethylmonothioarsinic acid (DMMTAV) and its active metabolite, dimethylarsinous acid (DMAIII), in HepaRG cells: Possibility of apoptosis cascade based on diversity of active metabolites of DMMTAV

Abstract Dimethylmonothioarsinical acid (DMMTA V ), a metabolite of arsenosugars (AsSug) and arsenolipids (AsLP), which are major organoarsenicals contained in seafoods, has been a focus of our attention due to its toxicity. It has been reported that the toxicity of DMMTA V differs according to the host cell type and that dimethylarsinous acid (DMA III ), which is a higher active metaboliteof inorganic and organo arsenic compounds, may be the ultimate substance. To further elucidate the details of the mechanisms of DMMTA V , we carried out toxicological characterization by comparing DMMTA V and DMA III using HepaRG cells, which are terminally differentiated hepatic cells derived from a human hepatic progenitor cell line that retains many characteristics, e.g, primary human hepatocytes including the morphology and expression of key metabolic enzymes (P450 s and GSTs, etc.) and complete expression of all nuclear receptors. HepaRG cells were induced to undergo differentiation by DMSO, which result red in increased levels of metabolic enzymes such as P450 and GST, in non-differentiated cells the cellular toxicities of DMMTA V and DMA III were reduced and the induction of toxicity by DMMTA V was increased by GSH but not by DMA III . Both DMA III and DMMTA V induce apoptosis and increase caspase 3/7 activity. DMA III exposure increased the activity of caspase-9. On the contrary, DMMTA V exposure resulted in markedly elevated activity of caspase-8as well as caspase-9. These results suggest there are differences between the signaling pathways of apoptosis in DMA III and DMMTA V and that between their active metabolites. Consequently, the ultimate metabolic substance of toxicity induction of DMMTA V may not only be DMA III , but may also be partly due to other metabolic substances produced through the activation mechanism by GSH.