PT  - JOURNAL ARTICLE
AU  - Elke Dopp
AU  - Ursula von Recklinghausen
AU  - Louise M. Hartmann
AU  - Inga Stueckradt
AU  - Ilona Pollok
AU  - Sasan Rabieh
AU  - Liping Hao
AU  - Andreas Nussler
AU  - Cindy Katier
AU  - Alfred V. Hirner
AU  - Albert W. Rettenmeier
TI  - Subcellular Distribution of Inorganic and Methylated Arsenic Compounds in Human Urothelial Cells and Human Hepatocytes
AID  - 10.1124/dmd.107.019034
DP  - 2008 May 01
TA  - Drug Metabolism and Disposition
PG  - 971--979
VI  - 36
IP  - 5
4099  - http://dmd.aspetjournals.org/content/36/5/971.short
4100  - http://dmd.aspetjournals.org/content/36/5/971.full
SO  - Drug Metab Dispos2008 May 01; 36
AB  - 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 American Society for Pharmacology and Experimental Therapeutics