https://zenodo.org/record/1229982/files/article.pdf

Recent advances in arsenic carcinogenesis: modes of action, animal model systems, and methylated arsenic metabolites.

Arsenic is widely distributed in nature in air, water and soil in the form of either metalloids or chemical compounds. It is used commercially, as pesticide, wood preservative, in the manufacture of glass, paper and semiconductors. Epidemiological and clinical studies indicate that arsenic is a paradoxical human carcinogen that does not easily induce cancer in animal models. It is one of the toxic compounds known in the environment. Intermittent incidents of arsenic contamination in ground water have been reported from several parts of the world. Arsenic containing drinking water has been associated with a variety of skin and internal organ cancers. The wide human exposure to this compound through drinking water throughout the world causes great concern for human health. In the present review, we have attempted to evaluate and update the mutagenic and genotoxic effects of arsenic and its compounds based on available literature.

Genetic toxicology of a paradoxical human carcinogen, arsenic: a review.

(1986). Clinical and Environmental Aspects of Arsenic Toxicity. CRC Critical Reviews in Clinical Laboratory Sciences: Vol. 23, No. 4, pp. 315-347.

Clinical and environmental aspects of arsenic toxicity.

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.

Arsenic toxicity is enzyme specific and its affects on ligation are not caused by the direct inhibition of DNA repair enzymes

CHAPTER 7 – The toxicity of arsenic and its compounds

Chromosome analysis of lymphocytes from patients who had been exposed to arsenic showed frequent structural and numerical aberrations, even with an interval of decades since the last exposure. The in vitro addition of sodium arsenate induced the same chromosome changes--even to extreme of chromosome pulverizations--upon lymphocyte cultures from healthy subjects. Radioactive incorporation studies showed that arsenate was able to inhibit dose-dependently the incorporation of radioactively labeled nucleotide in RNA and DNA. Beyond that, arsenic blocked the cells in the S- and G2-phase. A general explanation for the inhibitory effect of inorganic arsenic on cell metabolism is the known strong affinity of arsenic to enzymes, especially to those containing sulfhydryl groups.

Diethart Baron

Papers

Effects of arsenic cell metabolism and cell proliferation: cytogenetic and biochemical studies.