In vitro toxicological characterisation of the S-containing arsenic metabolites thio-dimethylarsinic acid and dimethylarsinic glutathione.
Inorganic arsenic is a well-documented, exposure relevant human carcinogen. A promising starting point to further understand the mechanisms behind inorganic arsenic carcinogenicity might be a formation of reactive, highly toxic metabolites during human arsenic metabolism. This study characterises the toxicity of recently identified S-containing arsenic metabolites in cultured human A549 lung adenocarcinoma epithelium cells. In direct comparison to arsenite, thio-dimethylarsinic acid (thio-DMA(V)) and dimethylarsinic glutathione (DMAG) exerted a 5- to 20-fold stronger cytotoxicity and showed a 2- to 20-fold higher cellular bioavailability, respectively. All three arsenicals disturbed cell cycle progression at cytotoxic concentrations, but failed to increase the level of reactive oxygen and nitrogen species (RONS) in healthy A549 cells. However, a strong disturbance of the oxidative defense system was observed after incubation with absolutely sub-cytotoxic, pico- to nanomolar concentrations of arsenite and thio-DMA(V), respectively. Thus, both GSH and GSSG levels were significantly decreased by up to 40%. Accordingly, RONS levels of oxidatively (H2O2) stressed cells were strongly increased by the arsenicals. Since in vivo RONS are permanently endogenously and exogenously produced, this boost of the existing oxidative stress by arsenite and thio-DMA(V) might contribute to the process of inorganic arsenic induced carcinogenicity.
Graduate School of Chemistry, Westfälische Wilhelms-Universität Muenster, Wilhelm-Klemm-Straße 10, 48149 Muenster, Germany; Institute of Food Chemistry, Westfälische Wilhelms-Universität Muenster, Corrensstraße 45, 48149 Muenster, Germany.
Larissa
L
Leffers
Marlies
M
Unterberg
Marc
M
Bartel
Cornelia
C
Hoppe
Imke
I
Pieper
Julia
J
Stertmann
Franziska
F
Ebert
Hans-Ulrich
HU
Humpf
Tanja
T
Schwerdtle
D018053:Arsenites / Q000494:pharmacology; D001682:Biological Availability; D002101:Cacodylic Acid / Q000031:analogs & derivatives* / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005978:Glutathione / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology
D018053:Arsenites; D002273:Carcinogens; C523062:thio-dimethylarsinate; D002101:Cacodylic Acid; D006861:Hydrogen Peroxide; D005978:Glutathione; C015001:arsenite