Comparative toxicity of arsenite metabolites in wild type CHO cells and in cells deficient in excision repair cross-complementing 1 and 2.
Arsenic (As) has been shown to alter one or more DNA repair processes. Excision repair cross-complementing 1 and 2 (ERCC1 and ERCC2) have shown to be associated with arsenic-induced toxicity and carcinogenicity. In this study, we investigated cytotoxic effects of various As metabolites in relation to two nucleotide excision repair genes: ERCC1 and ERCC2. Various arsenate (pentavalent) and arsenite (trivalent) metabolites were tested in ERCC1, ERCC2 deficient and wild type cells. Our results showed that in the selected concentration range pentavalent As metabolites; iAs(V), MMA(V) and DMA(V) were not cytotoxic, unlike the trivalent As metabolites; iAs(III), MMA(III) and DMA(III). The measured LC(50) demonstrated a significant difference (p<0.01) for iAs(III) between the three cell lines, while MMA(III) and DMA(III) are more cytotoxic to all three cell lines. UV5 (ERCC2 deficient) cells also showed a lower resistance to iAs(III) in comparison to AA8 (wild type) and UV20 (ERCC2 deficient) cells. This might be explained through the generation of hydrogen peroxide (H(2)O(2)), which is generated by increase of intracellular Ca(2+) level. Generation of H(2)O(2) in UV5 cells after incubation with iAs(III) is significantly higher than AA8 and UV20 cells (p<0.01). In conclusion, absence of ERCC2 leads to a increased generation of H(2)O(2) by iAs(III) in UV5 cells, which is in contrast to AA8 and UV20 cells.
Vahidnia
A
A
Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, L1-P Albinusdreef 2, Leiden, The Netherlands. ali.vahidnia@gmail.com
Pablo
R F
RF
van der Voet
G B
GB
van der Straaten
R J H M
RJ
de Wolff
F A
FA
D000818:Animals; D018053:Arsenites / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity*; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D004268:DNA-Binding Proteins / Q000187:drug effects* / Q000378:metabolism; D004720:Endonucleases / Q000187:drug effects* / Q000378:metabolism; D004785:Environmental Pollutants / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007928:Lethal Dose 50; D051759:Xeroderma Pigmentosum Group D Protein / Q000187:drug effects* / Q000378:metabolism
D018053:Arsenites; D004268:DNA-Binding Proteins; D004785:Environmental Pollutants; D006861:Hydrogen Peroxide; C071447:ERCC1 protein, human; D004720:Endonucleases; D051759:Xeroderma Pigmentosum Group D Protein; C497292:ERCC2 protein, human; D002118:Calcium