Methylation and Demethylation of Dimethylarsinic Acid in Rats Following Chronic Oral Exposure

Chen, Hua; Yoshida, Kaoru; Wanibuchi, Hideki; Fukushima, Shoji; Inoue, Yasuhiro; Endo, Ginji

doi:10.1002/(sici)1099-0739(199611)10:9<741::aid-aoc551>3.0.co;2-9

Cited by 23 publications

(12 citation statements)

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“…In vivo laboratory studies conducted 15-20 years ago report that DMA(V) is excreted in urine primarily unchanged after oral and parenteral administration (Marafante et al, 1987;Vahter et al, 1984;Yamauchi and Yamamura, 1984). It was observed that 4-15% of the dose of DMA (V) administered orally was excreted as a trimethylarsenic compound in urine of the hamster (Marafante et al, 1987;Yamauchi and Yamamura, 1984), mouse (Marafante et al, 1987), rat (Chen et al, 1996;Yoshida et al, 1997Yoshida et al, , 1998 and man (Marafante et al, 1987). This compound has been identified as trimethylarsine oxide (TMAO) (Marafante et al, 1987;Yoshida et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

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

Hughes

Devesa

Adair

et al. 2008

Toxicology and Applied Pharmacology

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Dimethylarsinic acid (DMA(V)) is a rat bladder carcinogen and the major urinary metabolite of administered inorganic arsenic in most mammals. This study examined the disposition of pentavalent and trivalent dimethylated arsenic in mice after acute oral administration. Adult female mice were administered [(14)C]-DMA(V) (0.6 or 60 mg As/kg) and sacrificed serially over 24 h. Tissues and excreta were collected for analysis of radioactivity. Other mice were administered unlabeled DMA(V) (0.6 or 60 mg As/kg) or dimethylarsinous acid (DMA(III)) (0.6 mg As/kg) and sacrificed at 2 or 24 h. Tissues (2 h) and urine (24 h) were collected and analyzed for arsenicals. Absorption, distribution and excretion of [(14)C]-DMA(V) were rapid, as radioactivity was detected in tissues and urine at 0.25 h. For low dose DMA(V) mice, there was a greater fractional absorption of DMA(V) and significantly greater tissue concentrations of radioactivity at several time points. Radioactivity distributed greatest to the liver (1-2% of dose) and declined to less than 0.05% in all tissues examined at 24 h. Urinary excretion of radioactivity was significantly greater in the 0.6 mg As/kg DMA(V) group. Conversely, fecal excretion of radioactivity was significantly greater in the high dose group. Urinary metabolites of DMA(V) included DMA(III), trimethylarsine oxide (TMAO), dimethylthioarsinic acid and trimethylarsine sulfide. Urinary metabolites of DMA(III) included TMAO, dimethylthioarsinic acid and trimethylarsine sulfide. DMA(V) was also excreted by DMA(III)-treated mice, showing its sensitivity to oxidation. TMAO was detected in tissues of the high dose DMA(V) group. The low acute toxicity of DMA(V) in the mouse appears to be due in part to its minimal retention and rapid elimination.

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Section: Introductionmentioning

confidence: 99%

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

Hughes

Devesa

Adair

et al. 2008

Toxicology and Applied Pharmacology

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“…Moreover, DMA was found to be carcinogenic for the urinary bladder on long‐term exposure to rats 12. Monomethylarsonic acid (MMA) and trimethylarsine oxide (TMAO) are also related methylated metabolites of inorganic arsenate and arsenite 13–15…”

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confidence: 99%

Promoting effects of monomethylarsonic acid, dimethylarsinic acid and trimethylarsine oxide on induction of rat liver preneoplastic glutathione S‐transferase placental form positive foci: A possible reactive oxygen species mechanism

Nishikawa

Wanibuchi

Ogawa

et al. 2002

Intl Journal of Cancer

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Dimethylarsinic acid (DMA) is a major metabolite of inorganic arsenicals, which are epidemiologically significant chemicals in relation to liver cancer in mammals. The present study was conducted to determine the promoting effects of organic arsenicals related to DMA [monomethylarsonic acid (MMA) and trimethylarsine oxide (TMAO)] on rat liver carcinogenesis using a liver medium-term bioassay (the Ito test). Male, 10-week-old, F344 rats were given a single i.p. injection of diethylnitrosamine at a dose of 200 mg/kg b.w. as an initiator. Starting 2 weeks thereafter they received 100 ppm of MMA, DMA or TMAO in their drinking water, or no supplement as a control, for 6 weeks. All animals underwent 2/3 partial hepatectomy in week 3 after initiation. Quantification of glutathione S-transferase placental form (GST-P)-positive foci as preneoplastic lesions in liver sections revealed significantly increased numbers and areas in all 3 treated groups compared with controls. Hepatic microsome cytochrome P-450 content was markedly increased with all 3 arsenic treatments. Markedly elevated CYP 2B1 protein levels and CYP 2B1/2 mRNA levels were thus observed in all cases. The potency of promotion was similar for MMA, DMA and TMAO. Since hydroxyradicals were found to be generated in the relatively early phase while methylated arsenicals were metabolized in liver, the resultant oxidative stress might have promoted lesion development. © 2002 Wiley-Liss, Inc. Key words: arsenic; hepatocarcinogenesis enhancement; oxidative stress; cytochrome P-450Drinking water contamination by arsenicals remains a major public health problem in many parts of the world. Epidemiologic research on arsenic has demonstrated significantly higher standardized mortality rate for cancers of the kidney, liver and colon, with especially high rates in the skin, urinary bladder and lung. 1,2 For causal factors in arsenic epidemiology, the focus has been on inorganic arsenite (AsIII) and arsenate (AsV), but experimental evidence was limited until recently. 3 Methylation of inorganic arsenics has been considered to result in detoxication. Thus inorganic arsenicals are methylated into dimethylarsinic acid (DMA), which is then excreted from the human body via the urine. 4 However, DMA may induce mitotic arrest in V79 cells, with potent clastogenic effects in human fibroblast cells and DMA has caused aneuploidy in mouse bone marrow cells. [5][6][7] Recent research demonstrated a promotion potential for DMA in the urinary bladder, kidney, liver and thyroid gland using a multiorgan carcinogenesis bioassay in rats, and also for skin tumorigenesis in mice. 8,9 We have also established that DMA promotes urinary bladder and liver carcinogenesis in a dose-dependent manner. 10,11 Moreover, DMA was found to be carcinogenic for the urinary bladder on long-term exposure to rats. 12 Monomethylarsonic acid (MMA) and trimethylarsine oxide (TMAO) are also related methylated metabolites of inorganic arsenate and arsenite. [13][14][15] In the present study the 3 organic arsenics MMA...

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“…Previously, the As metabolic potency of mammalian gut microbiota has been investigated by Rowland and Davies, and the in vitro experiments indicated that rat gut bacteria could generate iAs III and DMA from iAs V [131]. Methylated and thiolated As species (MMA V , TMAO, TMAS, DMMTA, DMDTA V , MMTTA) were previously detected in experiments performed by incubating iAs with mouse gut microbiota [132–135]. As metabolism by human gut microbiota was also explored.…”

Section: Gut Microbiome and As Susceptibilitymentioning

confidence: 99%

Individual susceptibility to arsenic-induced diseases: the role of host genetics, nutritional status, and the gut microbiome

Chi

Gao

et al. 2018

Mamm Genome

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Arsenic (As) contamination in water or food is a global issue affecting hundreds of millions of people. Although As is classified as a group 1 carcinogen and is associated with multiple diseases, the individual susceptibility to As-related diseases is highly variable, such that a proportion of people exposed to As have higher risks of developing related disorders. Many factors have been found to be associated with As susceptibility. One of the main sources of the variability found in As susceptibility is the variation in the host genome, namely, polymorphisms of many genes involved in As transportation, biotransformation, oxidative stress response and DNA repair affect the susceptibility of an individual to As toxicity and then influence the disease outcomes. In addition, lifestyles and many nutritional factors, such as folate, vitamin C, and fruit, have been found to be associated with individual susceptibility to As-related diseases. Recently, the interactions between As exposure and the gut microbiome have been of particular concern. As exposure has been shown to perturb gut microbiome composition, and the gut microbiota has been shown to also influence As metabolism, which raises the question of whether the highly diverse gut microbiota contributes to As susceptibility. Here, we review the literature and summarize the factors, such as host genetics and nutritional status, that influence As susceptibility, and we also present potential mechanisms of how the gut microbiome may influence As metabolism and its toxic effects on the host to induce variations in As susceptibility. Challenges and future directions are also discussed to emphasize the importance of characterizing the specific role of these factors in inter-individual susceptibility to As-related diseases.

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Methylation and Demethylation of Dimethylarsinic Acid in Rats Following Chronic Oral Exposure

Cited by 23 publications

References 14 publications

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

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

Promoting effects of monomethylarsonic acid, dimethylarsinic acid and trimethylarsine oxide on induction of rat liver preneoplastic glutathione S‐transferase placental form positive foci: A possible reactive oxygen species mechanism

Individual susceptibility to arsenic-induced diseases: the role of host genetics, nutritional status, and the gut microbiome

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