Antimony impairs nucleotide excision repair: XPA and XPE as potential molecular targets.
Trivalent antimony is a known genotoxic agent classified as a possible human carcinogen by the International Agency for Research on Cancer (IARC) and as an animal carcinogen by the German MAK Commission. Nevertheless, the underlying mechanism for its genotoxicity remains elusive. Because of the similarities between antimony and arsenic, the inhibition of DNA repair has been a promising hypothesis. Investigations on the removal of DNA lesions now revealed a damage specific impairment of nucleotide excision repair (NER). After irradiation of A549 human lung carcinoma cells with UVC, a higher number of cyclobutane pyrimidine dimers (CPD) remained in the presence of SbCl(3), whereas processing of the 6-4 photoproducts (6-4PP) and benzo[a]pyrene diol epoxide (BPDE)-induced DNA adducts was not impaired. Nevertheless, cell viability was reduced in a more than additive mode after combined treatment of SbCl(3) with UVC as well as with BPDE. In search of the molecular targets, a decrease in gene expression and protein level of XPE was found, which is known to be indispensable for the recognition of CPD. Moreover, trivalent antimony was shown to interact with the zinc finger domain of XPA, another NER protein, since SbCl(3) mediated a concentration dependent release of zinc from a peptide consistent with this domain. In the cellular system, association of XPA to and dissociation from damaged DNA was diminished in the presence of SbCl(3). These results show for the first time that trivalent antimony interferes with proteins involved in nucleotide excision repair and partly impairs this pathway, pointing to an indirect mechanism in the genotoxicity of trivalent antimony.
Fachgebiet Lebensmittelchemie und Toxikologie, Institut fur Lebensmitteltechnologie und Lebensmittelchemie, Technische Universitat Berlin, Gustav-Meyer-Allee 25, Berlin, Germany.
Claudia
C
Grosskopf
Tanja
T
Schwerdtle
Leon H F
LH
Mullenders
Andrea
A
Hartwig
D000965:Antimony / Q000633:toxicity*; D001580:Benzopyrenes / Q000633:toxicity; D002273:Carcinogens / Q000633:toxicity*; D045744:Cell Line, Tumor; D018736:DNA Adducts / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects / Q000528:radiation effects; D004260:DNA Repair / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D014466:Ultraviolet Rays; D051760:Xeroderma Pigmentosum Group A Protein / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
D001580:Benzopyrenes; D002273:Carcinogens; C117669:DDB2 protein, human; D018736:DNA Adducts; D004268:DNA-Binding Proteins; C497314:XPA protein, human; D051760:Xeroderma Pigmentosum Group A Protein; D000965:Antimony