Arsenic toxicity is enzyme specific and its affects on ligation are not caused by the direct inhibition of DNA repair enzymes.
The molecular mechanism of arsenic toxicity is believed to be due to the ability of arsenite [As(III)] to bind protein thiols. Numerous studies have shown that arsenic is cytotoxic at micromolar concentrations. Micromolar As can also induce chromosomal damage and inhibit DNA repair. The mechanism of arsenic-induced genotoxicity is very important because arsenic is a human carcinogen, but not a mutagen, and there is a need to establish recommendations for safe levels of As in the environment. We have measured the dose-response for arsenic inhibition of several purified human DNA repair enzymes, including DNA polymerase beta, DNA ligase I and DNA ligase III and have found that most enzymes, even those with critical SH groups, are very insensitive to As. Many repair enzymes are activated by millimolar concentrations of As(III) and/or As(V). Only pyruvate dehydrogenase, one of eight purified enzymes examined so far, is inhibited by micromolar arsenic. In contrast to the purified enzymes, treatment of human cells in culture with micromolar arsenic produces a significant dose-dependent decrease in DNA ligase activity in nuclear extracts from the treated cells. However, the ligase activity in extracts from untreated cells is no more sensitive to arsenic than the purified enzymes. Our results show that direct enzyme inhibition is not a common toxic effect of As and that only a few sensitive enzymes are responsible for arsenic-induced cellular toxicity. Thus, arsenic-induced co-mutagenesis and inhibition of DNA repair is probably not the result of direct enzyme inhibition, but may be an indirect effect caused by As-induced changes in cellular redox levels or alterations in signal transduction pathways and consequent changes in gene expression.
Hu
Y
Y
Nelson Institute of Environmental Medicine and Kaplan Comprehensive Cancer Center, New York University Medical Center, Tuxedo 10987, USA.
Su
L
L
Snow
E T
ET
D001151:Arsenic / Q000633:toxicity*; D002478:Cells, Cultured; D011088:DNA Ligases / Q000037:antagonists & inhibitors* / Q000302:isolation & purification; D004260:DNA Repair / Q000187:drug effects*; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000633:toxicity*; D004798:Enzymes / Q000378:metabolism; D004926:Escherichia coli; D006801:Humans; D009153:Mutagens / Q000633:toxicity*; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors
D004791:Enzyme Inhibitors; D004798:Enzymes; D009153:Mutagens; D019853:O(6)-Methylguanine-DNA Methyltransferase; D004259:DNA-Directed DNA Polymerase; D010749:Phosphoprotein Phosphatases; D011088:DNA Ligases; D001151:Arsenic