Monomethylarsonous acid (MMA(III)) is more toxic than arsenite in Chang human hepatocytes

Methylation has been considered to be the primary detoxication pathway of i norganic arsenic. Inorganic arsenic is methylated by many, but not all anim al species, to monomethylarsonic acid (MMA(V)), monomethylarsonous acid (MM A(III)), and dimethylarsinic acid (DMA(V)). The As-V derivatives have been assumed to produce low toxicity, but the relative toxicity of MMA(III) rema ins unknown. In vitro toxicities of arsenate, arsenite, MMA(V), MMA(III) an d DMA(V) were determined in Chang human hepatocytes, Leakage of lactate deh ydrogenase (LDH) and intracellular potassium (K+) and mitochondrial metabol ism of the tetrazolium salt XTT were used to assess cytotoxicity due to ars enic exposure. The mean LC50 based on LDH assays in phosphate media was 6 m u M for MMA(III) and 68 mu M for arsenite. Using the assay for K+ leakage i n phosphate media, the mean LC50 was 6.3 mu M for MMA(III) and 19.8 mu M fo r arsenite. The mean LC50 based on the XTT assay in phosphate media was 13. 6 mu M for MMA(III) and 164 mu M for arsenite. The results of the three cyt otoxicity 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 meth ylation, is highly toxic and again raises the question as to whether methyl ation of inorganic arsenic is a detoxication process. (C) 2000 Academic Pre ss.