Mutation Research/Reviews in Genetic Toxicology最新文献

The nitrogen mustards are bifunctional alkylating agents which, although used extensively in cancer chemotherapy, are themselves highly carcinogenic. All nitrogen mustards induce monofunctional guanine-N7 adducts, as well as interstrand N7-N7 crosslinks involving the two guanines in GNC · GNC (5′ → 3′ / 5′ ← 3′) sequences. In addition, the aromatic mustards melphalan and chlorambucil also induce substantial alkylation at adenine N3, while cyclophosphamide forms phosphotriesters with relatively high frequency. Nitrogen mustards are genotoxic in virtually every assay, and produce a wide array of mutations, including base substitutions at both G · C and A · T base pairs, intragenic as well as multilocus deletions, and chromosomal rearrangements. Mutational spectra generated by these agents in various model systems vary widely, and no single lesion has been implicated as being primarily responsible for mustard-induced mutagenesis. On the contrary, adducts of both adenine and guanine, and monofunctional as well as bifunctional adducts, appear to be involved. Further, it is still not known which types of mutation are responsible for mustard-induced cancers, since no genes have yet been identified which are consistently altered in these malignancies.

Reports on an inverse relationship between the consumption of fresh vegetables and human gastrointestinal cancer have been followed by screening for the protective activity of a large number of plant extracts, including leafy vegetables. Chlorophyll is ubiquitous in all green plant parts. Chlorophyllins are derivatives of chlorophyll in which the central magnesium atom is replaced by other metals, such as cobalt, copper or iron. An attempt has been made in this article to review the relative efficacy of chlorophyll and chlorophyllin in modifying the genotoxic effects of various known toxicants.

Compounds with structures close to those of normal nucleosides or nucleobases may be incorporated into cells and then become constituent of their DNA. Proliferation of such cells could yield mutants. In this article, the current status of studies on such nucleoside and nucleobase analogs is described. Base mispairing mechanisms for these analogs are discussed in light of recent biochemical and biophysical findings.

2-Acetylaminofluorene and 2-aminofluorene are among the most intensively studied of all chemical mutagens and carcinogens. Fundamental research findings concerning the metabolism of 2-acetylaminofluorene to electrophilic derivatives, the interaction of these derivatives with DNA, and the carcinogenic and mutagenic responses that are associated with the resulting DNA damage have formed the foundation upon which much of genetic toxicity testing is based. The parent compounds and their proximate and ultimate mutagenic and carcinogenic derivatives have been evaluated in a variety of prokaryotic and eukaryotic assays for mutagenesis and DNA damage. The reactive derivatives are active in virtually all systems, while 2-acetylaminofluorene and 2-aminofluorene are active in most systems that provide adequate metabolic activation. Knowledge of the structures of the DNA adducts formed by 2-acetylaminofluorene and 2-aminofluorene, the effects of the adducts on DNA conformation and synthesis, adduct distribution in tissues, cells and DNA, and adduct repair have been used to develop hypotheses to understand the genotoxic and carcinogenic effects of these compounds. Molecular analysis of mutations produced in cell-free, bacterial, in vitro mammalian, and intact animal systems have recently been used to extend these hypotheses.

DNA precursor pool imbalances can elicit a variety of genetic effects and modulate the genotoxicity of certain DNA-damaging agents. These and other observations indicate that the control of DNA precursor concentrations is essential for the maintenance of genetic stability, and suggest that factors which offset this control may contribute to environmental mutagenesis and carcinogenesis. In this article, we review the biochemical and genetic mechanisms responsible for regulating the production and relative amounts of intracellular DNA precursors, describe the many outcomes of perturbations in DNA precursor levels, and discuss implications of such imbalances for sensitivity to DNA-damaging agents, population monitoring, and human diseases.

In bacterial systems and in mammalian in vitro cell cultures, inorganic arsenic has been found to potentiate the mutagenic action of UV as well as of a number of mutagenic agents, probably by interfering with the later steps of DNA-repair. The Drosophila wing spot test (SMART) was used to study the modulating action of inorganic arsenic on the recombinogenic and mutagenic effects of the alkylating agents ethylnitrosourea (ENU), methylmethane sulphonate (MMS), and ethylene oxide (EO) as well as of gamma-rays. It was found, that arsenic in this in vivo test system exerted an inhibitory effect on mitotic recombination induced by alkylating agents and gamma-irradiation. These results are in contrast to the synergistic effect of inorganic arsenic on point mutations and deletions as reported for human lymphocytes and primary fibroblasts. The reason for the discrepancy between the mammalian systems and Drosophila with respect to the modulating action of arsenic is discussed.