title: Subcellular distribution of inorganic and methylated arsenic compounds in human urothelial cells and human hepatocytes.
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.
authors.affiliation: Institute of Hygiene and Occupational Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. elke.dopp@uni-due.de
authors.forename: Elke
authors.initials: E
authors.lastname: Dopp
authors.forename: Ursula
authors.initials: U
authors.lastname: von Recklinghausen
authors.forename: Louise M
authors.initials: LM
authors.lastname: Hartmann
authors.forename: Inga
authors.initials: I
authors.lastname: Stueckradt
authors.forename: Ilona
authors.initials: I
authors.lastname: Pollok
authors.forename: Sasan
authors.initials: S
authors.lastname: Rabieh
authors.forename: Liping
authors.initials: L
authors.lastname: Hao
authors.forename: Andreas
authors.initials: A
authors.lastname: Nussler
authors.forename: Cindy
authors.initials: C
authors.lastname: Katier
authors.forename: Alfred V
authors.initials: AV
authors.lastname: Hirner
authors.forename: Albert W
authors.initials: AW
authors.lastname: Rettenmeier
mesh_terms: D001152:Arsenicals / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D020552:Comet Assay; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D013347:Subcellular Fractions / Q000378:metabolism; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D019459:Urothelium / Q000166:cytology*
chemical_list: D001152:Arsenicals; D017392:Thiobarbituric Acid Reactive Substances