Monomethylarsonous acid (MMAIII) is more toxic than arsenite in Chang human hepatocytes.

Abstract Methylation has been considered to be the primary detoxication pathway of inorganic arsenic. Inorganic arsenic is methylated by many, but not all animal species, to monomethylarsonic acid (MMA V ), monomethylarsonous acid (MMA III ), and dimethylarsinic acid (DMA V ). The As V derivatives have been assumed to produce low toxicity, but the relative toxicity of MMA III remains unknown. In vitro toxicities of arsenate, arsenite, MMA V , MMA III , and DMA V were determined in Chang human hepatocytes. Leakage of lactate dehydrogenase (LDH) and intracellular potassium (K + ) and mitochondrial metabolism of the tetrazolium salt XTT were used to assess cytotoxicity due to arsenic exposure. The mean LC50 based on LDH assays in phosphate media was 6 μM for MMA III and 68 μM for arsenite. Using the assay for K + leakage in phosphate media, the mean LC50 was 6.3 μM for MMA III and 19.8 μM for arsenite. The mean LC50 based on the XTT assay in phosphate media was 13.6 μM for MMA III and 164 μM for arsenite. The results of the three cytotoxicity assays (LDH, K + , and XTT) reveal the following order of toxicity in Chang human hepatocytes: MMA III > arsenite > arsenate > MMA V = DMA V . Data demonstrate that MMA III , an intermediate in inorganic arsenic methylation, is highly toxic and again raises the question as to whether methylation of inorganic arsenic is a detoxication process.