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Research ArticleArticle

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

Elke Dopp, Ursula von Recklinghausen, Louise M. Hartmann, Inga Stueckradt, Ilona Pollok, Sasan Rabieh, Liping Hao, Andreas Nussler, Cindy Katier, Alfred V. Hirner and Albert W. Rettenmeier
Drug Metabolism and Disposition May 2008, 36 (5) 971-979; DOI: https://doi.org/10.1124/dmd.107.019034
Elke Dopp
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Ursula von Recklinghausen
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Louise M. Hartmann
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Inga Stueckradt
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Ilona Pollok
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Sasan Rabieh
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Liping Hao
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Andreas Nussler
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Cindy Katier
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Alfred V. Hirner
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Albert W. Rettenmeier
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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.

Footnotes

  • This work was kindly supported by the German Research Foundation (DFG: Deutsche Forschungsgemeinschaft, Grant FOR 415).

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.107.019034.

  • ABBREVIATIONS: As3MT, As(+3 oxidation state)-methyltransferase; CHO-9, Chinese hamster ovary cells; HPLC-HG-AFS, high-performance liquid chromatography–hydride generation–atomic fluorescence spectrometry; ICP-MS, inductively coupled plasma-mass spectrometry; MDA, malondialdehyde; TBARS, thiobarbituric acid reactive substances; UROtsa, SV-40–transformed normal human urinary bladder epithelial cell line; PBS, phosphate-buffered saline; phH, primary human hepatocytes.

    • Received October 12, 2007.
    • Accepted January 31, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 36 (5)
Drug Metabolism and Disposition
Vol. 36, Issue 5
1 May 2008
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Research ArticleArticle

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

Elke Dopp, Ursula von Recklinghausen, Louise M. Hartmann, Inga Stueckradt, Ilona Pollok, Sasan Rabieh, Liping Hao, Andreas Nussler, Cindy Katier, Alfred V. Hirner and Albert W. Rettenmeier
Drug Metabolism and Disposition May 1, 2008, 36 (5) 971-979; DOI: https://doi.org/10.1124/dmd.107.019034

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Research ArticleArticle

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

Elke Dopp, Ursula von Recklinghausen, Louise M. Hartmann, Inga Stueckradt, Ilona Pollok, Sasan Rabieh, Liping Hao, Andreas Nussler, Cindy Katier, Alfred V. Hirner and Albert W. Rettenmeier
Drug Metabolism and Disposition May 1, 2008, 36 (5) 971-979; DOI: https://doi.org/10.1124/dmd.107.019034
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