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Searches for ultimate chemical carcinogens and their reactions with cellular macromolecules
Abstract:
Studies on a variety of chemical carcinogens have demonstrated that their ultimate reactive and carcinogenic forms are strong electrophiles. Some carcinogens, such as alkylating agents, are in their ultimate forms as administered, but most require metabolism to these active derivatives. The ultimate carcinogens react, usually non-enzymatically, with nucleophilic constituents in vivo. Of particular interest in regard to their possible importance in carcinogenesis have been the covalent interactions of these electrophilic reactants with cellular informational macromolecules, the DNAs, RNAs, and proteins. Current data are consistent with the idea that the initiation step of chemical carcinogenesis is a mutagenic event and is caused by alteration of DNA by the ultimate carcinogens. The nature of the carcinogen metabolite(s) involved in the promotion phase has not been determined, but there appears to be no requirement that they be electrophilic. The development of the concept of ultimate chemical carcinogens as strong electrophilic reactants is reviewed, especially with respect to the studies carried in the authors' laboratory.
Insights
Chemical carcinogens become active electrophiles that damage DNA, initiating cancer. Further research is needed to understand the promotion phase of carcinogenesis.
Area of Science:
- Biochemistry
- Toxicology
- Molecular Biology
Background:
- Chemical carcinogens require metabolic activation to reactive electrophilic forms.
- These electrophiles interact with cellular macromolecules like DNA, RNA, and proteins.
Purpose of the Study:
- To review the concept of ultimate chemical carcinogens as electrophilic reactants.
- To discuss their role in the initiation and promotion phases of chemical carcinogenesis.
Main Methods:
- Review of existing studies on chemical carcinogens and their metabolites.
- Analysis of covalent interactions between electrophilic carcinogens and cellular macromolecules.
Main Results:
- Ultimate carcinogens are strong electrophiles that react with nucleophiles in vivo.
- DNA alteration by ultimate carcinogens is implicated in the initiation of chemical carcinogenesis.
- The role of carcinogen metabolites in the promotion phase remains undetermined.
Conclusions:
- The initiation of chemical carcinogenesis is a mutagenic event caused by DNA alteration.
- Further investigation is required to elucidate the role of metabolites in the promotion phase.