Arsenite and its biomethylated metabolites interfere with the formation and repair of stable BPDE-induced DNA adducts in human cells and impair XPAzf and Fpg.
The underlying mechanisms of arsenic carcinogenicity are only poorly understood and especially the role of biomethylation is still a matter of debate. Besides the induction of oxidative DNA damage the interference with DNA repair processes have been proposed to contribute to arsenic-induced carcinogenicity. Within the present study the effects of arsenite and its mono- and dimethylated trivalent and pentavalent metabolites on BPDE-induced DNA adduct formation and repair has been investigated and compared in cultured human lung cells. Whereas only arsenite and MMA(III) increased BPDE-DNA adduct formation, arsenite (>/=5 microM), the trivalent (>/=2.5 microM) and the pentavalent (>/=250 microM) metabolites diminished their repair at non-cytotoxic concentrations. As potential molecular targets, interactions with the zinc finger domain of the human XPA protein (XPAzf) and the Escherichia coli zinc finger protein Fpg, involved in NER and BER, respectively, have been investigated. All trivalent arsenicals were able to release zinc from XPAzf; furthermore, MMA(III) and DMA(III) inhibited the activity of isolated Fpg. Altogether the results suggest that besides arsenite, especially the trivalent methylated metabolites may contribute to diminished NER at low concentrations.
Schwerdtle
Tanja
T
Institute of Food Chemistry and Toxicology, University of Karlsruhe, Postfach 6980, D-76128, Karlsruhe, Germany.
Walter
Ingo
I
Hartwig
Andrea
A
D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000009:adverse effects*; D018053:Arsenites / Q000009:adverse effects*; D002273:Carcinogens / Q000009:adverse effects; D002478:Cells, Cultured; D018736:DNA Adducts / Q000187:drug effects*; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D043382:DNA-Formamidopyrimidine Glycosylase / Q000378:metabolism*; D004926:Escherichia coli; D029968:Escherichia coli Proteins / Q000378:metabolism*; D006801:Humans; D008745:Methylation; D013723:Teratogens / Q000494:pharmacology; D051760:Xeroderma Pigmentosum Group A Protein; D015032:Zinc / Q000378:metabolism; D016335:Zinc Fingers
D018053:Arsenites; D002273:Carcinogens; D018736:DNA Adducts; D004268:DNA-Binding Proteins; D029968:Escherichia coli Proteins; D013723:Teratogens; C497314:XPA protein, human; D051760:Xeroderma Pigmentosum Group A Protein; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; D043382:DNA-Formamidopyrimidine Glycosylase; C468610:DNA-formamidopyrimidine glycosylase, E coli; D015032:Zinc; C015001:arsenite