Arsenite and its mono- and dimethylated trivalent metabolites enhance the formation of benzo[a]pyrene diol epoxide-DNA adducts in Xeroderma pigmentosum complementation group A cells.
Recently, inorganic arsenite (iAs(III)) and its mono- and dimethylated metabolites have been examined for their interference with the formation and repair of benzo[a]pyrene diol epoxide (BPDE)-induced DNA adducts in human cells (Schwerdtle, ., Walter, I., and Hartwig, A. (2003) DNA Repair 2, 1449 - 1463). iAs(III) and monomethylarsonous acid (MMA(III)) were found to be able to enhance the formation of BPDE-DNA adducts, whereas dimethylarsinous acid (DMA(III)) had no enhancing effect at all. The anomaly manifested by DMA(III) prompted us to further investigate the effects of the three trivalent arsenic species on the formation of BPDE-DNA adducts. Use of a nucleotide excision repair (NER)-deficient Xeroderma pigmentosum complementation group A cell line (GM04312C) allowed us to dissect DNA damage induction from DNA repair and to examine the effects of arsenic on the formation of BPDE-DNA adducts only. At concentrations comparable to those used in the study by Schwerdtle et al., we found that each of the three trivalent arsenic species was able to enhance the formation of BPDE-DNA adducts with the potency in a descending order of MMA(III) > DMA(III) > iAs(III), which correlates well with their cytotoxicities. Similar to iAs(III), DMA(III) modulation of reduced glutathione (GSH) or total glutathione S-transferase (GST) activity could not account for its enhancing effect on DNA adduct formation. Additionally, the enhancing effects elicited by the trivalent arsenic species were demonstrated to be highly time-dependent. Thus, although our study made use of short-term assays with relatively high doses, our data may have meaningful implications for carcinogenesis induced by chronic exposure to arsenic at low doses encountered environmentally.
Shen
Shengwen
S
Department of Laboratory Medicine and Pathology, 10-102 Clinical Sciences Building, University of Alberta, Edmonton, Alberta, Canada.
Lee
Jane
J
Cullen
William R
WR
Le
X Chris
XC
Weinfeld
Michael
M
D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000737:chemistry / Q000378:metabolism*; D018053:Arsenites / Q000494:pharmacology / Q000633:toxicity*; D002101:Cacodylic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D002460:Cell Line; D002461:Cell Line, Transformed; D018736:DNA Adducts / Q000378:metabolism*; D004249:DNA Damage; D004260:DNA Repair; D019075:Electrophoresis, Capillary; D005347:Fibroblasts / Q000187:drug effects; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D009942:Organometallic Compounds / Q000494:pharmacology / Q000633:toxicity*; D013997:Time Factors; D051760:Xeroderma Pigmentosum Group A Protein / Q000378:metabolism
C057268:7,8-dihydroxy-9,10-oxy-7,8,9,10-tetrahydrobenzo(a)pyrene-DNA adduct; D018053:Arsenites; D018736:DNA Adducts; D009942:Organometallic Compounds; D051760:Xeroderma Pigmentosum Group A Protein; C472511:dimethylarsinous acid; C406082:monomethylarsonous acid; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; D002101:Cacodylic Acid; D005982:Glutathione Transferase; C015001:arsenite