Arsenic, a common poison, is known to react with sulfide in vivo, forming thioarsenates. The acute toxicity of the inorganic thioarsenates is currently unknown. Our experiments showed that a fourfold sulfide excess reduced acute arsenite cytotoxicity in human hepatocytes (HepG2) and urothelial cells (UROtsa) significantly, but had little effect on arsenate toxicity. Speciation analysis showed immediate formation of thioarsenates (up to 73 % of total arsenic) in case of arsenite, but no speciation changes for arsenate. Testing acute toxicity of mono- and trithioarsenate individually, both thioarsenates were found to be more toxic than their structural analogue arsenate, but less toxic than arsenite. Toxicity increased with the number of thio groups. The amount of cellular arsenic uptake after 24 h corresponded to the order of toxicity of the four compounds tested. The dominant to almost exclusive intracellular arsenic species was arsenite. The results imply that thiolation is a detoxification process for arsenite in sulfidic milieus. The mechanism could either be that thioarsenates regulate the amount of free arsenite available for cellular uptake without entering the cells themselves, or, based on their chemical similarity to arsenate, they could be taken up by similar transporters and reduced rapidly intracellularly to arsenite.
Arsenic forms different species that are toxic for humans. Toxicity to internal organs is, however, only relevant if the respective species passes the gastrointestinal barrier. Thioarsenates were known to be produced by gut microbiota and to be toxic to bladder and liver cells, but their intestinal transport was largely unknown. Using a Caco-2 cell model, we show here that dimethylmonothioarsenate has the highest cellular retention and intestinal transport of all methylated species. Mono- and trithioarsenate show little cellular retention like arsenate, but their intestinal transport is much higher than that of arsenate; for trithioarsenate, it is almost as high as that for arsenite. The transport of all thioarsenates increases in the absence of phosphate. With the present study, we link previous reports of thioarsenate formation and toxicity by proving their bioavailability and confirm the relevance of their consideration in As risk assessments.
Based on acute cytotoxicity studies, selenosulfate (SeSO3 (-)) has been suggested to possess a generally higher toxic activity in tumor cells than selenite. The reason for this difference in cytotoxic activity remained unclear. In the present study, cytotoxicity tests with human hepatoma (HepG2), malignant melanoma (A375), and urinary bladder carcinoma cells (T24) showed that the selenosulfate toxicity was very similar between all three tested cell lines (IC50 6.6-7.1 μM after 24 h). It was largely independent of exposure time and presence or absence of amino acids. What changed, however, was the toxicity of selenite, which was lower than that of selenosulfate only for HepG2 cells (IC50 > 15 μM), but similar to and higher than that of selenosulfate for A375 (IC50 4.7 μM) and T24 cells (IC50 3.5 μM), respectively. Addition of amino acids to T24 cell growth medium downregulated short-term selenite uptake (1.5 versus 12.9 ng Se/10(6) cells) and decreased its cytotoxicity (IC50 8.4 μM), rendering it less toxic than selenosulfate. The suggested mechanism is a stronger expression of the xc (-) transport system in the more sensitive T24 compared to HepG2 cells which creates a reductive extracellular microenvironment and facilitates selenite uptake by reduction. Selenosulfate is already reduced and so less affected. The cytotoxic activity of selenosulfate and selenite to tumor cells therefore depends on the sensitivity of each cell line, supplements like amino acids as well as the reductive state of the extracellular environment.
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