A concise review of the toxicity and carcinogenicity of dimethylarsinic acid

Abstract

Dimethylarsinic acid (DMA) has been used as a herbicide (cacodylic acid) and is the major metabolite formed after exposure to tri-(arsenite) or pentavalent (arsenate) inorganic arsenic (iAs) via ingestion or inhalation in both humans and rodents. Once viewed simply as a detoxification product of iAs, evidence has accumulated in recent years indicating that DMA itself has unique toxic properties. DMA induces an organ-specific lesion -single strand breaks in DNA -in the lungs of both mice and rats and in human lung cells in vitro. Mechanistic studies have suggested that this damage is due mainly to the peroxyl radical of DMA and production of active oxygen species by pulmonary tissues. Multi-organ initiation-promotion studies have demonstrated that DMA acts as a promotor of urinary bladder, kidney, liver and thyroid gland cancers in rats and as a promotor of lung tumors in mice. Lifetime exposure to DMA in diet or drinking water also causes a dose-dependent increase in urinary bladder tumors in rats, indicating that DMA is a complete carcinogen. These data collectively suggest that DMA plays a role in the carcinogenesis of inorganic arsenic. Published by Elsevier Science Ireland Ltd.Keywords: Arsenic; Cancer; Dimethylarsinic acid www.elsevier.com/locate/toxicol Dimethylarsinic acid 1 (DMA; see Fig. 1) has been used as a herbicide and is also the major metabolite formed after exposure to trivalent (arsenite, AsIII) or pentavalent (arsenate, AsV) inorganic arsenic via ingestion or inhalation in both humans and most rodents (US EPA, 1975; ATSDR, 1993). Methylation of inorganic arsenic to form both DMA and methylarsonic acid (MMA) has traditionally been viewed as a mechanism to facilitate the detoxification and excretion of arsenic. This is principally because DMA, in particular, is over 10-fold less acutely toxic than inorganic arsenic (Kaise et al., 1985(Kaise et al., , 1989. However, evidence suggesting that DMA itself has unique toxic properties has accumulated in the * Corresponding author. Tel.: +1-919-5410043; fax: +1-919-5415394.E-mail address: kenyon.elaina@epa.gov (E.M. Kenyon). 1 Unless specifically stated otherwise, the abbreviation DMA refers to pentavalent dimethyl form of arsenic. The distinction is important because emerging evidence suggests that both trivalent monomethylated arsenic and trivalent DMA are more tissue-reactive and cytotoxic than their pentavalent counterparts.0300-483X/01/$ -see front matter Published by Elsevier Science Ireland Ltd. PII: S 0 3 0 0 -4 8 3 X ( 0 0 ) 0 0 4 5 8 -3

Caveolin-Induced Activation of the Phosphatidylinositol 3-Kinase/Akt Pathway Increases Arsenite Cytotoxicity

“…Indeed, we observed that caveolin overexpression is associated with elevated forkhead phosphorylation (data not shown). Given that arsenite's toxic effects are mediated in large part through oxidative stress (14), this could be an important factor in the increased susceptibility of caveolin-overexpressing cells.…”

“…Here we have examined the influence of caveolin expression on the cellular response to treatment with the tumor promoter arsenite (4,5,14). Our results indicate that caveolin overexpression leads to an increase in Akt activation, possibly through the diminished synthesis of ceramide, a lipid that was previously shown to inhibit PI3K activity (43).…”

Subcellular Distribution of Inorganic and Methylated Arsenic Compounds in Human Urothelial Cells and Human Hepatocytes

“…Genotoxicity of arsenic species does not involve direct interaction with DNA. It has been suggested that indirect processes such as oxidative damage evoked by reactive oxygen species (Basu et al, 2001;Gebel, 2001;Kenyon and Hughes, 2001;Liu et al, 2001Liu et al, , 2005Ahmad et al, 2002;Nesnow et al, 2002;Kitchin and Ahmad, 2003;) and the inhibition of DNA repair (Hughes, 2002;Rossman, 2003;Schwerdtle et al, 2003a) are implicated.…”

Biokinetics and Subchronic Toxic Effects of Oral Arsenite, Arsenate, Monomethylarsonic Acid, and Dimethylarsinic Acid in v-Ha-ras Transgenic (Tg.AC) Mice

“…Humans are exposed primarily to trivalent [arsenite, As(III)] and pentavalent [arsenate, As(V)] inorganic arsenicals present in the environment, as well as to organic arsenic [e.g., dimethylarsinic acid, DMA(V)] in some situations (Kenyon and Hughes 2001;Shen et al 2003b). In mammals, As(V) is first reduced to As(III), whereas As(III), produced by this reduction or from direct ingestion, is methylated primarily to pentavalent organic arsenicals including monomethylarsonic acid [MMA(V)] and DMA(V)].…”