Disease relevance of cacodylic acid

• Methylmercury poisoning (e.g., Minamata disease) and tumor development in rats after exposure to dimethylarsinic acid or tributyltin oxide are just some examples [1].
• We have mainly studied arsenite [As(III)], arsenate [As(V)], monomethylarsonic acid (MMAA), and dimethylarsinic acid (DMAA) because these are the most commonly used biomarkers of exposure by the general population to inorganic arsenic and because of concerns over these arsenic species on their toxicity and carcinogenicity [2].
• Dimethylarsinic acid (DMA), fed to rats for 2 years, produced bladder hyperplasia and tumors at doses of 40 and 100 p.p.m., more in females than males [3].
• The cytotoxicity and genotoxicity of the bacteria-free solution of dimethylarsinic acid or trimethylarsine oxide metabolized by E. coli A3-6 were studied using V79 cells [4].
• METHODS AND RESULTS: We investigated the antiproliferative and cytotoxic activity of dimethylarsinic acid (DMAA), an organic arsenic derivative and major metabolic by-product of As(2)O(3), against a panel of eight leukemia and multiple myeloma cell lines [5].

High impact information on cacodylic acid

• To various degrees, ingested inorganic arsenic (InAs) is methylated to monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) via folate-dependent one-carbon metabolism; impaired methylation is associated with adverse health outcomes [6].
• Carcinogenicity of dimethylarsinic acid in p53 heterozygous knockout and wild-type C57BL/6J mice [7].
• Effects of dietary dimethylarsinic acid on the urine and urothelium of rats [3].
• Preferential increase of heterochromatin in venular endothelium of lung in mice after administration of dimethylarsinic acid, a major metabolite of inorganic arsenics [8].
• Dimethylarsinic acid (DMAA) administration induced the preferential increase of the heterochromatic area forming the inside of the interphase nucleus [8].

Chemical compound and disease context of cacodylic acid

• The reaction of dimethylarsinic acid (DMAV) with hydrogen sulfide (H2S) is of biological significance and may be implicated in the overall toxicity and carcinogenicity of arsenic [9].
• Methylation of inorganic arsenic (iAs) to monomethylarsonic acid (MMA(V)) and dimethylarsinic acid (DMA(V)) is considered to decrease arsenic toxicity [10].
• The capacity for inorganic arsenic (ASi) methylation in 13 healthy volunteers and in 30 patients with different types of liver disease has been assessed by measuring the amount of unmetabolized ASi, monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) excreted in urine within 24 h after the IV injection of 7.14 micrograms/kg ASi [11].

Biological context of cacodylic acid

• DNA damage induced in cultured human alveolar (L-132) cells by exposure to dimethylarsinic acid [12].
• A major human arsenic metabolite, dimethylarsinic acid, requires reduced glutathione to induce apoptosis [13].
• Because of the low absolute bioavailability of dimethylarsinic acid and the high proportion of dimethylarsinic acid in greenhousegrown rice, only 33 +/- 3% (mean +/- SD) of the total ricebound arsenic was bioavailable [14].
• The methylation of inorganic arsenic to monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) have been generally considered to be the major pathway for inorganic arsenic biotransformation and detoxification [15].
• Inorganic arsenic and dimethylarsinic acid (DMA) were the main arsenic species in rice grain for six genotypes, and there were large genotypic differences in levels of DMA and inorganic arsenic in grain [16].

Anatomical context of cacodylic acid

• Our long-term oral administration of dimethylarsinic acid (DMAV) in rats revealed that three unidentified metabolites, M-1, M-2, and M-3, were detected in urine and feces [17].
• By using this sequential-enzyme-digestion comet assay, we demonstrated that trivalent inorganic arsenic induced more DNA damage than monomethylarsonous acid, monomethylarsonic acid, and dimethylarsinic acid in human blood cell lines [18].
• Role of mitotic motors, dynein and kinesin, in the induction of abnormal centrosome integrity and multipolar spindles in cultured V79 cells exposed to dimethylarsinic acid [19].
• Aneuploidy induced by dimethylarsinic acid in mouse bone marrow cells [20].
• DNA-protein cross-links and sister chromatid exchanges induced by dimethylarsinic acid in human fibroblasts cells [21].

Associations of cacodylic acid with other chemical compounds

• To assess the arsenic exposure of a population living in the vicinity of a coal-burning power plant with high arsenic emission in the Prievidza District, Slovakia, 548 spot urine samples were speciated for inorganic As (Asinorg), monomethylarsonic acid (MMA), dimethylarsinic acid (DMA), and their sum (Assum) [22].
• High-performance liquid chromatogram inductively coupled plasma mass spectrometry was used to speciate arsenic species [Arsenite [As(III)], arsenate [As(V)], monomethylarsonic acid [MMA(V)], monomethylarsonous acid [MMA(III)], dimethylarsinic acid [DMA(V)], and arsenobetaine [AsB]] in aqueous standards and in urine samples [23].
• Therefore, both inorganic arsenite and organic dimethylarsinic acid induce apoptosis in cerebellar neurons, with the inorganic form being more toxic [24].
• Yet, when arsenate/arsenite is injected into the Callithrix jacchus (marmoset) monkey or chimpanzee, monomethylarsonic acid and dimethylarsinic acid are not found in the urine [15].
• We have proposed that oral administration of dimethylarsinic acid (DMA), a metabolite of inorganic arsenics in mammals, rather than inorganic arsenics themselves, promotes lung and skin tumors by way of the metabolic production of free radicals such as dimethylarsenic peroxy radical [(CH(3))(2)AsOO*] [25].

Gene context of cacodylic acid

• Promotion of skin carcinogenesis by dimethylarsinic acid in keratin (K6)/ODC transgenic mice [26].
• In vitro experiments suggested that trivalent inorganic arsenic (iAsIII) but not pentavalent arsenicals including iAsV, monomethylarsonic acid (MMAsV), and dimethylarsinic acid (DMAsV) affected the hepatic TR activity of rabbit [27].
• When human alveolar epithelial type II (L-132) cells in culture were exposed to either one of these three arsenic compounds, DNA single-strand breaks resulting from the inhibition of repair polymerization were remarkably produced by exposure to DMAA at 5 to 100 microM, while not by that to ARS and MMAA even at 100 microM [28].
• Metallothionein (I/II) suppresses genotoxicity caused by dimethylarsinic acid [29].
• Promotion of rat hepatocarcinogenesis by dimethylarsinic acid: association with elevated ornithine decarboxylase activity and formation of 8-hydroxydeoxyguanosine in the liver [30].

Analytical, diagnostic and therapeutic context of cacodylic acid

• The present study was conducted to determine the carcinogenicity of dimethylarsinic acid (DMA) administered to male F344 rats in a 2 year bioassay [31].
• Urinary sulfur-containing metabolite produced by intestinal bacteria following oral administration of dimethylarsinic acid to rats [17].
• Dimethylarsinic acid, one of organic arsenics, was found to be carcinogenic in rat bladder using DMBDD model and carcinogenicity test [32].
• We investigated the cytogenetic effects of dimethylarsinic acid (DMA), which is the major metabolite of inorganic arsenic compounds, on mouse bone marrow cells after a single intraperitoneal injection to mice [20].
• Simultaneous determination of dimethylarsinic acid and monomethylarsonic acid after derivatization with thioglycol methylate by gas chromatography/mass spectrometry [33].

References