Mechanism of comutagenesis of sodium arsenite with n-methyl-n-nitrosourea.
Arsenic compounds are known carcinogens. Although many carcinogens are also mutagens, we have previously shown that sodium arsenite is not mutagenic at either the Na+/K+ ATPase or hprt locus in Chinese hamster V79 cells. It can, however, enhance UV-mutagenesis. We now confirm the nonmutagenicity of sodium arsenite in line G12, a pSV2gpt-transformed V79 (hprt-) cell line, which is able to detect multilocus deletions in addition to point mutations and small deletions. The lack of arsenic mutagenicity has led to studies emphasizing its comutagenicity. Sodium arsenite at relatively nontoxic concentrations (5 microM for 24 h or 10 microM for 3 h) is comutagenic with N-methyl-N-nitrosourea (MMU) at the hprt locus in V79 cells. Using a nick translation assay, which measures DNA strand breaks by incorporating radioactive deoxyribonucleoside monophosphate at their 3'OH ends in permeabilized cells, we found that much more incorporation was seen in cells treated with MNU (4 mM, 15 min) followed by 3-h incubation with 10 microM sodium arsenite compared with cells exposed to the same MNU treatment followed by 3-h incubation without sodium arsenite. This result shows that in the presence of arsenite, strand breaks resulting from MNU or its repair accumulate over a 3-h period. We suggest that the repair of MNU-induced DNA lesions may be inhibited by arsenite either by affecting the incorporation of dNMPs into the MNU-damaged DNA template or by interfering with the ligation step.
Li
J H
JH
Institute of Environmental Medicine, New York University Medical Center, NY 10016.
Rossman
T G
TG
D000818:Animals; D001151:Arsenic / Q000633:toxicity*; D018053:Arsenites; D002478:Cells, Cultured; D006224:Cricetinae; D004926:Escherichia coli / Q000201:enzymology / Q000235:genetics; D008770:Methylnitrosourea / Q000633:toxicity*; D009153:Mutagens; D010957:Plasmids; D014176:Protein Biosynthesis; D017670:Sodium Compounds; D014162:Transfection
D018053:Arsenites; D009153:Mutagens; D017670:Sodium Compounds; C017947:sodium arsenite; D008770:Methylnitrosourea; D001151:Arsenic