Methylated trivalent arsenicals as candidate ultimate genotoxic forms of arsenic: Induction of chromosomal mutations but not gene mutations

Abstract

Arsenic is a prevalent human carcinogen whose mutagenicity has not been characterized fully. Exposure to either form of inorganic arsenic, As(III) or As(V), can result in the formation of at least four organic metabolites: monomethylarsonic acid, monomethylarsonous acid (MMA(III)), dimethylarsinic acid, and dimethylarsinous acid (DMA(III)). The methylated trivalent species, as well as some of the other species, have not been evaluated previously for the induction of chromosome aberrations, sister chromatid exchanges (SCE), or toxicity in cultured human peripheral blood lymphocytes; for mutagenicity in L5178Y/Tk(+/-) mouse lymphoma cells or in the Salmonella reversion assay; or for prophage-induction in Escherichia coli. Here we evaluated the arsenicals in these assays and found that MMA(III) and DMA(III) were the most potent clastogens of the six arsenicals in human lymphocytes and the most potent mutagens of the six arsenicals at the Tk(+/-) locus in mouse lymphoma cells. The dimethylated arsenicals were also spindle poisons, suggesting that they may be ultimate forms of arsenic that induce aneuploidy. Although the arsenicals were potent clastogens, none were potent SCE inducers, similar to clastogens that act via reactive oxygen species. None of the six arsenicals were gene mutagens in Salmonella TA98, TA100, or TA104; and neither MMA(III) nor DMA(III) induced prophage. Our results show that both methylated As(V) compounds were less cytotoxic and genotoxic than As(V), whereas both methylated As(III) compounds were more cytotoxic and genotoxic than As(III). Our data support the view that MMA(III) and DMA(III) are candidate ultimate genotoxic forms of arsenic and that they are clastogens and not gene mutagens. We suggest that the clastogenicity of the other arsenicals is due to their metabolism by cells to MMA(III) or DMA(III).

TP53 alterations and patterns of carcinogen exposure in a U.S. population‐based study of bladder cancer

“…17,53,54 Indeed, there is also experimental evidence supporting our observation of an absence of TP53 mutations in arsenic-exposed individuals. 55 Thus, our data are in agreement with the hypothesis that arsenic contributes to bladder cancer through a pathway that does not involve TP53 mutation or inactivation that leads to persistent staining. Clearly, further data at low exposure levels are needed.…”

Metabolism and toxicity of arsenic in human urothelial cells expressing rat arsenic (+3 oxidation state)-methyltransferase

“…In contrast, methylated trivalent arsenicals, methylarsonous acid (MAs III ) and dimethylarsonous acid (DMAs III ), are more toxic than iAs in vivo (Petrick et al, 2001) and are more potent than iAs as enzyme inhibitors (Lin et al, 2001;Petrick et al, 2001;, cytotoxins (Petrick et al, 2000;Styblo et al, 2000, and as modulators of cell signaling pathways (Drobná et al, 2003;. In addition, MAs III and DMAs III are more potent than iAs as DNA-damaging agents in vitro and in cultured cells (Kligerman et al, 2003;Mass et al, 2001). Thus, MAs III and DMAs III formed in the course of iAs methylation likely contribute to the toxicity and cancerpromoting effects associated with acute and chronic exposures to iAs.…”

Tissue dosimetry, metabolism and excretion of pentavalent and trivalent monomethylated arsenic in mice after oral administration

“…MMA(III) was a more potent cytotoxicant than arsenite in human Chang liver cells (Petrick et al, 2000), human hepatocytes (Styblo et al, 2000) and several other human and rodent cell types (Styblo et al, 2000). MMA(III) was a direct-acting genotoxin, whereas MMA(V) was not active (Andrewes et al, 2003;Kligerman et al, 2003;Mass et al, 2001). The chronic effects of exposure to MMA(III) are not known.…”