The molecular mechanism of arsenic carcinogenesis
Arsenic compounds are known human carcinogens. Although many carcinogens are also mutagens, arsenite is not mutagenic in the V79 (hprt and Na{sup +}/K{sup +} ATPase) system or in the G12 (qpt) system. This clearly indicates that arsenite per se does not cause any type of mutation detectable at these loci, including point mutations, small deletions and multilocus deletions. The lack of arsenic mutagenesis has led to studies emphasizing its comutagenicity. In this study, arsenite was found to enhance both UV- and MNU-mutagenesis in V79 or G12 cells. Although arsenite is comutagenic with both UV{sub 254} and UV{sub 360}, the latter seems more important because of its natural relevance. The ability of arsenite to inhibit the repair of MNU-induced DNA damage was measured by a nick translation assay which measures DNA strand breaks by incorporating radioactive dNMP at their 3{prime}OH ends in permeabilized V79 cells. It was found that strand breaks resulting from MNU or its repair accumulate in the presence of arsenite. MNU-induced poly(ADP-ribose) synthesis, measured by the incorporation of ({sup 3}H)NAD{sup +} in permeabilized cells, was also increased by post-treatment of the cells with arsenite. This supports the hypothesis that arsenite inhibits the completion of DNA repair. The accumulated strand breaks in the presence of arsenite are probably not due to direct inhibition of DNA polymerase {alpha}, the presumed repair enzyme, since very high concentrations of arsenite are needed. DNA polymerase {beta} and DNA ligase are probably not the direct targets of arsenite for a similar reason. Thus arsenite probably inhibits the completion of DNA repair in an indirect way. Arsenite per se can inhibit metabolic cooperation and it can induce SV40 gene amplification. This suggests arsenite might also function as a tumor-promoter.
- Research Organization:
- New York Univ., NY (United States)
- OSTI ID:
- 5505148
- Country of Publication:
- United States
- Language:
- English
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560120 -- Radiation Effects on Biochemicals
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560300* -- Chemicals Metabolism & Toxicology
59 BASIC BIOLOGICAL SCIENCES
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
ANIMAL CELLS
ANIMALS
ARSENIC
BIOLOGICAL RECOVERY
BIOLOGICAL REPAIR
CARBONIC ACID DERIVATIVES
CARCINOGENESIS
COENZYMES
DNA
DNA POLYMERASES
DNA REPAIR
ELECTROMAGNETIC RADIATION
ELEMENTS
ENZYMES
GENE AMPLIFICATION
HAMSTERS
HYDROGEN COMPOUNDS
ISOTOPE APPLICATIONS
LIGASES
MAMMALS
METHYL NITROSOUREA
MUTAGENESIS
MUTAGENS
NAD
NITROSO COMPOUNDS
NUCLEIC ACIDS
NUCLEOTIDES
NUCLEOTIDYLTRANSFERASES
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
PATHOGENESIS
PHOSPHORUS-GROUP TRANSFERASES
POLYMERASES
RADIATIONS
RADIOINDUCTION
RADIOSENSITIVITY EFFECTS
RECOVERY
REPAIR
RODENTS
SEMIMETALS
STRAND BREAKS
TRACER TECHNIQUES
TRANSFERASES
TRITIUM COMPOUNDS
ULTRAVIOLET RADIATION
VERTEBRATES