Quantitative structure-activity relationships of heterocyclic amine mutagens formed during the cooking of food.
The major protein-rich foods, particularly muscle meats, contain part-per-billion quantities of potent mutagens formed by frying or broiling to a well-done state. Related mutagens are formed by pyrolysis of amino acids or proteins and in heated model systems. The thermic mutagens so far identified are heterocyclic aromatic amines of aminoimidazo-azaarene (AIA) and aminocarboline classes. The chemicals require activation by enzymes to form metabolites reactive with nucleic acids. These thermic mutagens, and numerous synthetic congeners, exhibit an enormous range of potency as frameshift mutagens in the Ames/Salmonella assay. However, structural variations are nominal within the two classes. Structural parameters that appeared relevant to determining potency were selected for 38 AIAs and 23 amino-carbolines. For the AIA class these were: the number of fused rings, the number of heteroatoms in Rings 2 and 3, methyl substitution on imidazo ring nitrogen atoms, and methyl substitution on ring carbon atoms. For the amino-carboline class the structural parameters were: the position of the pyridine-type nitrogen atom in Ring 1, the substitution position of the exocyclic amino group on Ring 1, and methyl substitution on ring carbon atoms. These structural parameters may influence mutagenic potency in the following ways. 1) Electronic or steric effects may determine the reactivity and stability of the ultimate mutagenic metabolite. Optimal balance of reactivity and lifetime of this transient intermediate may be required for access to and reaction with nuclear DNA to cause mutations. 2) Substitution on the rings may block detoxication reactions. The structural parameters identified should prove useful in predicting the mutagenicity of untested compounds of these types.
Hatch
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Biomedical Sciences Division, Lawrence Livermore National Laboratory, California.
Knize
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MG
Felton
J S
JS
D000588:Amines / Q000032:analysis*; D000818:Animals; D001391:Azo Compounds / Q000032:analysis; D002243:Carbolines / Q000032:analysis; D005504:Food Analysis; D006571:Heterocyclic Compounds / Q000032:analysis* / Q000494:pharmacology; D006358:Hot Temperature; D006801:Humans; D008460:Meat / Q000032:analysis; D009152:Mutagenicity Tests; D009153:Mutagens / Q000032:analysis*; D012486:Salmonella typhimurium / Q000187:drug effects; D013329:Structure-Activity Relationship
D000588:Amines; D001391:Azo Compounds; D002243:Carbolines; D006571:Heterocyclic Compounds; D009153:Mutagens