The role of active arsenic species produced by metabolic reduction of dimethylarsinic acid in genotoxicity and tumorigenesis

Yamanaka, Kazuhiro; Kato, Koichi; Mizoi, Mutsumi; An, Yan; Takabayashi, Fumiyo; Nakano, Masayuki; Hoshino, Mikio; Okada, Shoji

doi:10.1016/j.taap.2003.10.025

Cited by 60 publications

(31 citation statements)

References 44 publications

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“…Several studies have implicated oxidative stress and free radical formation as important factors in the genotoxicity and cytotoxicity of arsenic compounds (Kitchin, Kitchin and Ahmad, 2003;Schwerdtle et al, 2003b;Shi et al, 2004;Yamanaka et al, 2004). Disruption of tubulin polymerization by arsenicals is also discussed in the literature (Kligerman et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

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

Dopp

Recklinghausen²,

Hartmann³

et al. 2008

Drug Metab Dispos

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ABSTRACT:Epidemiological studies have indicated that exposure of humans to inorganic arsenic in drinking water is associated with the occurrence of bladder cancer. The mechanisms by which arsenic induces this malignancy are still uncertain; however, arsenic metabolites are suspected to play a pivotal role. The aim of the present study was the investigation of uptake capabilities of human urothelial cells (UROtsa) compared with primary human hepatocytes (phH) as well as the intracellular distribution of the arsenic species. Additionally, we were interested in the cyto-and genotoxic potential (comet assay, radical generation) of the different arsenic compounds in these two cell types. Our results show that UROtsa cells accumulate higher amounts of the arsenic species than the phH. Differential centrifugation revealed that the arsenic compounds are preferentially distributed into nuclei and ribosomes. After 24-h exposure, arsenic is mainly found in the ribosomes of UROtsa cells and in the nuclei and mitochondria of phH. In contrast to the pentavalent arsenic species, the trivalent species induced a 4-to 5-fold increase of DNA damage in hepatocytes. Radical generation, measured by thiobarbituric acid reactive substances, was more pronounced in hepatocytes than in urothelial cells. In summary, the uptake of arsenic compounds appears to be highly dependent upon cell type and arsenic species. The nonmethylating urothelial cells accumulate higher amounts of arsenic species than the methylating hepatocytes. However, cyto-and genotoxic effects are more distinct in hepatocytes. Further studies are needed to define the implications of the observed accumulation in cellular organelles for the carcinogenic activity of arsenic.The association between arsenic exposure and urinary bladder cancer, typically transitional cell carcinomas, has been observed in the same endemic areas of the world in which skin cancer populations have been identified (Chiou et al., 1995). In addition to bladder and skin cancer, chronic arsenic exposure causes several malignant and nonmalignant human diseases [for review, see Tseng (2007) (Challenger, 1945) consists of a series of reductions and oxidative methylations. In the sequence of reactions, the ϩ5 oxidative arsenic species are always formed before the analogous ϩ3 arsenic species.Recently, Hayakawa et al. (2005) proposed a new metabolic pathway for arsenic biotransformation in which the ϩ3 arsenic species are formed before the respective ϩ5 species. The trivalent metabolites are oxidized by hydrogen peroxide or other agents to the pentavalent species, which are considered end products of arsenic metabolism.It is generally accepted that the ϩ3 methylated arsenic species are more cyto-and genotoxic (e.g., Styblo et al., 2000;Mass et al., 2001;Aposhian et al., 2003;Kligerman et al., 2003;Dopp et al., 2004) and are more potent enzyme inhibitors (e.g., Styblo et al., 1997aStyblo et al., , 2002Schuliga et al., 2002;Chang et al., 2003) than the pentavalent counThis work was kindly supported by the Ge...

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Section: Discussionmentioning

confidence: 99%

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

Dopp

Recklinghausen²,

Hartmann³

et al. 2008

Drug Metab Dispos

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“…Furthermore, some organoarsenicals such as DMA(V) and DMA(III), as well as inorganic arsenic, show carcinogenic action, probably by inducing oxidative stress (Kitchin 2001;Kitchin and Ahmad 2003;Hei and Filipic 2004). DMA(V) may be a carcinogen and tumor promoter in some experimental animals (Yamanaka et al 2004). Presumably, dimethylarsenic peroxide may act as a tumor promoter and the dimethylarsenic radical and dimethylarsenic peroxy radical act as tumor-initiating factors, all of which seem to be metabolites of DMA(V) (Yamanaka et al 2004).…”

Section: Toxicological Significance Of Arsenic In Marine Mammals Seamentioning

confidence: 99%

“…DMA(V) may be a carcinogen and tumor promoter in some experimental animals (Yamanaka et al 2004). Presumably, dimethylarsenic peroxide may act as a tumor promoter and the dimethylarsenic radical and dimethylarsenic peroxy radical act as tumor-initiating factors, all of which seem to be metabolites of DMA(V) (Yamanaka et al 2004). In HeLa S3 cells, As(III) induced oxidative DNA damage at 0.075 µg ml −1…”

Section: Toxicological Significance Of Arsenic In Marine Mammals Seamentioning

confidence: 99%

Arsenic in Marine Mammals, Seabirds, and Sea Turtles

Kunito

Kubota

Fujihara

et al. 2008

Reviews of Environmental Contamination and Toxicology

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“…These metabolites are less reactive in tissue constituents than iAs and are readily excreted in urine. However, reactive intermediates of trivalent MMA and DMA (MMA III and DMA III ) produced in iAs metabolic processing in mammals may be responsible for the observed carcinogenic effects [6][7][8][9]. Therefore, in 2010, the IARC classified MMA and DMA as group 2B compounds, and arsenobetaine (AsBe) and other organic arsenic compounds that are not metabolized in humans as group 3 compounds [10].…”

Section: Introductionmentioning

confidence: 99%

Arsenic speciation analysis of urine samples from individuals living in an arsenic-contaminated area in Bangladesh

Hata

Yamanaka

Habib

et al. 2011

Environ Health Prev Med

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Objectives Chronic inorganic arsenic (iAs) exposure currently affects tens of millions of people worldwide. To accurately determine the proportion of urinary arsenic metabolites in residents continuously exposed to iAs, we performed arsenic speciation analysis of the urine of these individuals and determined whether a correlation exists between the concentration of iAs in drinking water and the urinary arsenic species content. Methods The subjects were 165 married couples who had lived in the Pabna District in Bangladesh for more than 5 years. Arsenic species were measured using high-performance liquid chromatography and inductively coupled plasma mass spectrometry. Results The median iAs concentration in drinking water was 55 lgAs/L (range \0.5-332 lgAs/L). Speciation analysis revealed the presence of arsenite, arsenate, monomethylarsonic acid (MMA), and dimethylarsinic acid in urine samples with medians (range) of 16.8 (7.7-32.3), 1.8 (\0.5-3.3), 13.7 (5.6-25.0), and 88.6 lgAs/L (47.9-153.4 lgAs/L), respectively. No arsenobetaine or arsenocholine was detected. The concentrations of the 4 urinary arsenic species were significantly and linearly related to each other. The urinary concentrations of total arsenic and each species were significantly correlated with the iAs concentration of drinking water. Conclusions All urinary arsenic species are well correlated with each other and with iAs in drinking water. The most significant linear relationship existed between the iAs concentration in drinking water and urinary iAs ? MMA concentration. From these results, combined with the effects of seafood ingestion, the best biomarker of iAs exposure is urinary iAs ? MMA concentration.

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The role of active arsenic species produced by metabolic reduction of dimethylarsinic acid in genotoxicity and tumorigenesis

Cited by 60 publications

References 44 publications

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

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

Arsenic in Marine Mammals, Seabirds, and Sea Turtles

Arsenic speciation analysis of urine samples from individuals living in an arsenic-contaminated area in Bangladesh

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