Structural characteristics of compounds that can be activated to chemically reactive metabolites: use for a prediction of a carcinogenic potential.
Many mutagens and carcinogens act via covalent interaction of metabolic intermediates with DNA in the target cell. This report groups those structural elements which are often found to form the basis for a metabolism to such chemically reactive metabolites. Compounds which are chemically reactive per se and which do not require metabolic activation form group 1. Group 2 comprises of olefins and aromatic hydrocarbons where the oxidation via an epoxide can be responsible for the generation of reactive species. Aromatic amines, hydrazines, and nitrosamines form group 3 requiring an oxidation of a nitrogen atom or of a carbon atom in alpha position to a nitrosated amine. Group 4 compounds are halogenated hydrocarbons which can either give rise to radicals or can form an olefin (group 2) upon dehydrohalogenation. Group 5 compounds depend upon some preceding enzymatic activity either not available in the target cell or acting on positions in the molecule which are not directly involved in the subsequent formation of electrophilic atoms. Examples for each group are taken from the "List of Chemicals and Industrial Processes Associated with Cancer in Humans" as compiled by the International Agency for the Research on Cancer, and it is shown that 91% of the organic carcinogens would have been detected on the basis of structural elements characteristic for group 1-5. As opposed to this very high sensitivity, the specificity (the true negative fraction) of using this approach as a short-term test for carcinogenicity is shown to be bad because detoxification pathways have so far not been taken into account. These competing processes are so complex, however, that either only very extensive knowledge about pharmacokinetics, stability, and reactivity will be required or that in vivo systems have to be used to predict, on a quantitative basis, the damage expected on the DNA. DNA-binding experiments in vivo are presented with benzene and toluene to demonstrate one possible way for an experimental assessment and it is shown that the detoxification reaction at the methyl group available only in toluene gives rise to a reduction by at least a factor of forty for the binding to rat liver DNA. This quantitative approach available with DNA-binding tests in vivo, also allows evaluation as to whether reactive metabolites and their DNA binding are always the most important single activities contributing to the overall carcinogenicity of a chemical.(ABSTRACT TRUNCATED AT 400 WORDS)
D000818:Animals; D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism* / Q000633:toxicity; D055598:Chemical Phenomena; D002621:Chemistry; D004247:DNA / Q000378:metabolism; D006838:Hydrocarbons / Q000378:metabolism / Q000633:toxicity; D006846:Hydrocarbons, Halogenated / Q000378:metabolism / Q000633:toxicity; D009584:Nitrogen / Q000378:metabolism / Q000633:toxicity; D009602:Nitrosamines / Q000378:metabolism / Q000633:toxicity; D010084:Oxidation-Reduction; D013329:Structure-Activity Relationship
D002273:Carcinogens; D006838:Hydrocarbons; D006846:Hydrocarbons, Halogenated; D009602:Nitrosamines; D004247:DNA; D009584:Nitrogen