Mutation Research/Reviews in Genetic Toxicology最新文献

1-Ethyl-1-nitrosourea (ENU) is a potent monofunctional ethylating agent that has been found to be mutagenic in a wide variety of mutagenicity test systems from viruses to mammalian germ cells. It also has been shown to induce tumors in various organs of mammals.

ENU has been used only for research purposes. ENU possesses the dual action of ethylation and carbamoylation. The ethyl group can be transferred to nucleophilic sites of cellular constituents, and the carbonyl group can be transferred to an amino group of a protein. ENU is able to produce significant levels of alkylation at oxygens, such as the O⁶ position of guanine and the O⁴ position of thymine of DNA. The molecular genetic data obtained from ENU-induced mutants on various species suggest that ENU produces mainly GC-AT transitions and, to a small extent, AT-GC, AT-CG, AT-TA, GC-CG and GC-TA base substitutions. This mutation spectrum of ENU is different from that of 1-methyl-1-nitrosourea, which mainly induces GC-AT transitions.

ENU is a most potent mutagen in mouse germ cells, especially in stem-cell spermatogonia. It induces intragenic mutations with high frequency in male mouse germ cells. ENU has been established as a model compound for exploring the effects of chemical mutagenesis on mouse germ cells.

55 published articles were identified which reported results of tests of ELF (extremely low frequency) or static electric or magnetic fields for genotoxic effects. The biological assays used spanned a wide range, including microbial systems, plants, Drosophila, mammalian and human cells in vitro and in vivo. Experimental results were grouped into four exposure categories: ELF Electric; ELF Magnetic; Static Electric; and Static Magnetic. The internal electric fields present in media (for in vitro experiments) and in the torso and extremities (for in vivo experiments) were estimated, providing an index of comparison. All experiments were critically analyzed with respect to basic data quality criteria. Experiments within each exposure category were then compared to determine if results reinforced or contradicted one another. The preponderance of evidence suggests that neither ELF nor static electric or magnetic fields have a clearly demonstrated potential to cause genotoxic effects. However, there may be genotoxic activity from exposure under conditions where phenomena auxiliary to an electric field, such as spark discharges, electrical shocks, or corona can occur. In addition, two unconfirmed reports suggest the genotoxic potential of certain chemical mutagens or ionizing radiation may be affected by co-exposure to electric or magnetic fields. Certain exposure categories are not represented or are under-represented by tests in some genotoxicity test systems that are usually included in minimal test batteries as specified by EPA for chemicals. It is suggested that consideration be given to whether additional genotoxicity testing is warranted to fill these gaps.

Pine cone extract fraction VI (PC-VI) inhibited the mutagenicity of the promutagens tested: the polycyclic aromatic hydrocarbon benzo[a]pyrene (B[a]P) dose-dependently, and the aromatic amines 2-aminoanthracene (AA) and 2-acetylaminofluorene (AAF) at high concentrations. PC-VI had no effect on the mutagenicity of the direct-acting mutagens 2-(2-furyl)-3-(5-nitrofuryl)acrylamide (AF-2) and N-methyl-N′-nitro-N-nitrosoguanidine (MNNG), but inhibited the mutagenicity of the direct-acting mutagen N-hydroxy 2-acetylaminofluorene (N-OH AAF, proximate mutagen of AAF). The addition of PC-VI to rat hepatic microsomes resulted in a decrease of their enzyme activities, especially NADPH-cytochrome c reductase. By gas-chromatographic analysis of B[a]P or AA contents after incubation of B[a]P or AA and PC-VI and S9 mix, the inhibition of hepatic metabolizing enzymes and the interaction between AA and PC-VI were confirmed. On the other hand, PC-VI had no effect on the DNA repair systems for B[a]P- or AA-induced mutagenesis.

We conclude that PC-VI shows indirect antimutagenicity by interfering with cytochrome P-450-dependent bioactivation and by direct interaction with AA and the proximate mutagenic product of AAF.

The halogenated pyrimidines were synthesized in the 1950s as potential anti-tumor agents after the discovery that certain tumors preferentially incorporated uracil rather than thymine into the DNA. The fluorinated derivatives are widely recognized today as effective treatment modalities, especially with tumors of the head, neck and breast. Mechanistically, efficacy of the fluorinated pyrimidines results from the ability of these compounds to incoporporate into RNA and inhibit its maturation to those forms necessary for cellular metabolism and from the inhibition of the enzyme, thymidylate synthetase, which controls the biosynthesis of thymine and DNA synthesis. The 5-fluoropyrimidines can incorporate into DNA, but the contribution of this phenomenon to the overall efficacy of this class of chemotherapeutic agents is not totally resolved. Evidence exists that this class of compounds possesses the properties to induce genotoxic effects, both in bacterial and eukaryotic cells. Most notably, these effects include the induction of cellular toxicity and the induction of chromosome aberrations. The biology and chemistry of the chlorinated pyrimidines were first explored as a possible means of sensitizing the DNA to ionizing radiation in a manner similar to the sensitization observed when DNA incorporates bromodeoxyuridine. This approach was not utilized clinically. The genetic toxicology of this compound became important with the discovery of the ribonucleoside in the effluents of sewage treatment plants. Evidence is now available that the chlorinated pyrimidines, upon conversion to deoxyribonucleosides, are effective mutagens, clastogens and toxicants, as well as extremely effective inducers of sister-chromatid exchanges.

Epidemiologic studies have reported a modestly increased risk of childhood leukemia associated with certain electric power wire configurations. Since cancer likely involves DNA damage, this review discusses the evidence of direct and indirect genetic toxicity effects for both electric and magnetic fields at 50- and 60-Hz and miscellaneous pulsed exposures. Exposure conditions vary greatly among different end points measured, making comparisons and conclusions among experiments difficult. Although most of the available evidence does not suggest that electric and/or magnetic fields cause DNA damage, the existence of some positive findings and limitations in the set of studies carried out suggest a need for additional work.