Mutation Research/Reviews in Genetic Toxicology最新文献

A wide variety of oxidative DNA lesions are commonly present in untreated human and animal DNA. One of these lesions, 8-hydroxydeoxyguanosine, has been shown to lead to base mispairing (mutation) on DNA replication. Other lesions remain to be investigated in this respect. Oxidative DNA lesions on cell replication may, in appropriate circumstances, lead to proto-oncogene activation. Oxidative DNA damage, on fixation, may also lead to cytotoxicity followed by regenerative proliferation. The probable or possible importance of oxidative DNA damage is reviewed for various classes of carcinogens and natural processes, including metal ions, high-energy radiation, miscellaneous chemicals, tumor-promoting agents, polyhydroxyphenols/quinones, lipid metabolism, peroxisome proliferators and thyroid function. It is concluded that although the evidence needs considerable strengthening in many of these examples, the available information indicates the potential importance of oxidative DNA damage in the induction of tumors by these agents. It is also possible that non-cancerous degenerative diseases associated with aging are the result of the accumulation of lesions resulting from unrepaired oxidative DNA damage.

The SOS chromotest is reviewed through over 100 publications corresponding to the testing of 751 chemicals. 404 (54%) of these chemicals present a genotoxic activity detectable in the SOS chromotest. Their SOS inducing potencies span more than 8 orders of magnitude.

For 452 compounds, the results obtained in the SOS chromotest could be compared to those obtained in the Ames test. It was found that 373 (82%) of these compounds give similar responses in both tests (236 positive and 137 negative responses). Thus the discrepancies between both tests concern 79 compounds (18%). A case by case analysis shows that many of these compounds are at the same time very weak SOS inducers and very weak mutagens. Thus we think that, most of the time, the discrepancies between the two tests may be accounted for by differences in the interpretation of the results rather than by the experimental results themselves. However, there are some compounds which are clearly SOS inducers but devoid of mutagenic activity in the Ames test (such as quinoline-1-oxide) and to a larger extent, clearly mutagenic compounds which do not induce the SOS response in the SOS chromotest (such as benzidine, cyclophosphamide, acridines, ethidium bromide).

We also analyzed the correlation between SOS induction, mutagenesis and carcinogenesis according to the classification of Lewis. For 65 confirmed carcinogens (class 1), the sensitivity, i.e., the capacity to identify carcinogens, was 62% with the SOS chromotest and 77% with the Ames test. For 44 suspected carcinogens (class 2), the sensitivity was 66% with the SOS chromotest and 68% with the Ames test.

Thus, we confirmed previous observations made on 83 compounds that there is a close correlation between the results given by both bacterial tests. The capacity of the Ames test to identify carcinogens is higher than that of the SOS chromotest. However, because the number of false positive compounds was lower in the SOS chromotest, the specificity, i.e., the capacity to discriminate between carcinogens and non-carcinogens of the SOS chromotest, appeared higher than that of the Ames test. Thus, the results of the SOS chromotest and of the Ames test can complement each other.

The SOS chromotest is one of the most rapid and simple short-term test for genotoxins and is easily adaptable to various conditions, so that it could be used as an early - perhaps the earliest - test in a battery.

AB2497 and its mutS and umuDC derivatives were EMS-treated at the stationary phase and specificity of mutation measured. It was found that: (i) in mutS⁺ cells EMS induces predominantly GC → AT transitions (by supB or supE(oc) formation) and in mutS⁻ cells mainly AT → TA transversions (by supL(NG) formation); (ii) transversions of AT → TA are umuDC-dependent and mutational specificity is biased towards AT → GC transitions in mutS⁻umuDC⁻ strains. When mutS⁻umuDC⁻ cells were transfected with plasmids bearing umuD'C or umuDC genes, mutational specificity was again biased towards AT → TA transversions; (iii) experiments with bacteria bearing umuC::lacZ or recA::lacZ fusions suggest that processing of UmuD → UmuD' might be poorer in EMS-treated mutS⁻ than in mutS⁺ cells.

In this paper, we considered rodent carcinogenicity and toxicity, and four in vitro mutagenicity systems, and we made a global comparison between their different response profiles to a common set of 297 chemicals. This analysis is complemented with a study of the physical chemical properties of active and inactive compounds in the different systems.

A clearcut separation between the different classes of toxicological end-points (carcinogenicity, in vivo toxicity, in vitro carcinogenicity) was evident. The observed lack of association between carcinogenicity and toxicity supports the validity of the rodent bioassays; this is contrary to the position that the positive results obtained are due mainly to the use of excessive doses that exert cytotoxic effects. We found substantial consistency in the responses of the in vivo toxicity systems (maximum tolerated dose and LD₅₀), but we also found that remarkable differences exist between the in vitro mutagenicity assay systems. The study of the structure-activity relationships showed that: (a) the hydrophobic-electronic properties of the chemicals influence rodent carcinogenicity, with the tendency of carcinogens to be more electrophilic and more hydrophobic than non-carcinogens; (b) steric effects are implied in in vitro mutagenicity, bulkier molecules being less mutagenic than smaller molecules; (c) no clear association between in vivo toxicity and physical chemical properties was apparent. The differences between carcinogenicity and in vitro mutagenicity may hypothetically be related to their different experimental procedures. The relatively short treatment of in vitro mutagenicity requires that chemicals penetrate easily into the cells, and are well dissolved into the aqueous medium, size and hydrophilicity thus being critical for the action of the chemicals. The size of the molecules is not critical in the long-term rodent carcinogenicity experiments, where other factors, like bioaccumulation (hydrophobicity) and electronic reactivity, become essential.

Gossypol, a polyphenolic compound extracted from cotton plants, shows promise for use as a male contraceptive, as well as a treatment for gynecological disorders, cancer, and certain microbial diseases. Before gossypol can be considered safe for widespread human use, particularly by healthy people of childbearing age, its effect on normal genetic processes should be understood. Characterization of gossypol's genotoxic potential has not been approached systematically, although numerous clinical and laboratory studies have addressed issues relating to genetic effects of gossypol. This review summarizes results of relevant studies and offers recommendations for the emphasis of future efforts to understand gossypol's genotoxicity potential. Evidence suggesting that gossypol has any genotoxic effects in mammals under normal physiologic conditions so far is weak, at best. However, several unresolved issues that are important for establishing long-term genetic safety of gossypol were uncovered by this analysis. These include the need for a better understanding of the significance of weak increases in SCE frequency seen in a number of laboratory exposure studies, and more definitive, comprehensive animal tumor bioassay data.

Parties interested in registering a pesticide chemical with the U.S. Environmental Protection Agency's (USEPA's) Office of Pesticide Programs (OPP) must submit toxicity information to support the registration. Mutagenicity data are a part of the required information that must be submitted. This information is available to the public via Freedom of Information requests to the OPP. However, it is felt that this information would be more effectively and widely disseminated if presented in a published medium. Beginning with this publication, sets of mutagenicity data on pesticide chemicals will be periodically published in the Genetic Activity Profile (GAP) format. In addition, mutagenicity data extracted from the currently available open literature is also presented to provide a more complete database and to allow comparisons between the OPP-submitted data and other publicly available information.

This paper reviews the ability of a number of chemicals to induce sister-chromatid exchanges (SCEs). The SCE data for animal cells in vivo and in vitro, and human cells in vitro are presented in 6 tables according to their relative effectiveness. A seventh table summarizes what is known about the effects of specific chemicals on SCEs for humans exposed in vivo. The data support the concept that SCEs provide a useful indication of exposure, although the mechanism and biological significance of SCE formation still remain to be elucidated.