ABSTRACT
An isomeric series of heterocyclic amines related to one found in heated muscle meats was investigated for properties that predict their measured mutagenic potency. Eleven of the 12 possible 2-amino-trimethylimidazopyridine (TMIP) isomers were tested for mutagenic potency in the Ames/Salmonella test with bacterial strain TA98, and resulted in a 600-fold range in potency. Structural, quantum chemical, and hydropathic data were calculated on the parent molecules and the corresponding nitrenium ions of all of the tested isomers to establish models for predicting the potency of the unknown isomer. The principal determinants of higher mutagenic potency in these amines are: (1) a small dipole moment, (2) the combination of b-face ring fusion and N3-methyl group, (3) a lower calculated energy of the pi electron system, (4) a smaller energy gap between the amine HOMO and LUMO orbitals (Pearson "softness"), and (5) a more stable nitrenium ion. Based on predicted potency from the average of six regression models, the isomer not yet synthesized and tested is expected to have a mutagenic potency of 0.77 revertants/microg in tester strain TA98, which is near the low end of the potency range of the isomers.
Subject(s)
Computer Simulation , Models, Statistical , Pyridines/chemistry , Pyridines/toxicity , Quantitative Structure-Activity Relationship , Salmonella/drug effects , Isomerism , Molecular Structure , Mutagenicity TestsABSTRACT
Mixtures of the free amino acids, creatine and glucose, were dry-heated to model the potential formation of heterocyclic amines in meats. The formation of the mutagenic amine IFP (determined to be 2-amino-(1,6-dimethylfuro[3,2-e]imidazo[4,5-b])pyridine) was investigated by varying heating time, heating temperature, and precursors. With an optimized mixture of glutamine, creatine, and glucose, heated at 200 degrees C for 60 min, 2 mg of IFP was purified for studies to define its structure. Trideuteriomethyl-IFP was made from trideuteriomethylcreatinine in the model system for use in LC-MS detection of IFP in foods. Analysis of well-done meats purchased from restaurants showed about half to contain IFP at levels from 1.4 to 46 ng/g of cooked meat, demonstrating human exposure to this mutagen.
Subject(s)
Furans/chemistry , Imidazoles/chemistry , Meat/analysis , Mutagens/chemistry , Cooking , Furans/analysis , Imidazoles/analysis , Mutagens/analysis , RestaurantsABSTRACT
The occurrence and formation of heterocyclic amines in foods is discussed in light of the consistent finding of a new class of imidazopyridines. In addition, a quantitative structure-activity relationship will be presented correlating the potency of these imidazopyridines to predicted chemical properties. Although no strong linear correlation is found between the potency and the chemical properties, a low dipole moment is found to be a qualitative predictor of high mutagenic potency.
Subject(s)
Imidazoles/chemistry , Mutagens/chemistry , Pyridines/chemistry , Imidazoles/toxicity , Mutagenicity Tests , Mutagens/toxicity , Pyridines/toxicity , Structure-Activity RelationshipABSTRACT
The mutagenic activity of 3 aza-polycyclic aromatic hydrocarbons, which are suspected of being environmental pollutants, was assessed using the Salmonella assay. The compounds tested were phenanthro[9,10-g]isoquinoline, phenanthro[2,3-h]isoquinoline, and phenanthro[3,2-h]isoquinoline. None of the compound was mutagenic in the absence of S9, but all were mutagenic in the presence of S9.
Subject(s)
Isoquinolines/pharmacology , Mutagens , Phenanthrenes/pharmacology , Biotransformation , Microsomes, Liver/metabolism , Mutagenicity Tests , Salmonella typhimurium/drug effectsABSTRACT
The mutagenic and carcinogenic activities of 5 azapyrenes, which are suspected of being environmental pollutants, were assessed using the Salmonella assay and the anchorage-independent survival assay. The compounds tested were: 1-azapyrene, 2-azapyrene, 4-azapyrene, 1-aza-2-hydroxypyrene, and 2-aza-1-hydroxypyrene. The compounds were mutagenic and some were also carcinogenic.
Subject(s)
Cell Survival/drug effects , Environmental Pollutants/toxicity , Mutagens/toxicity , Mutation/drug effects , Pyrenes/toxicity , Animals , Cell Aggregation/drug effects , Cell Line , Dose-Response Relationship, Drug , Mutagenicity Tests , Rats , Structure-Activity RelationshipABSTRACT
The potential carcinogenicity of 3 azabenz(a)anthracenes was determined in vitro. The 3 compounds tested were 1-, 2-, and 9-azabenz(a)anthracene. The initial assay was chemical carcinogen-induced enhancement of anchorage-independent survival of Rauscher leukemia virus-infected Fischer rat embryo cells, 2FR(4)50 (2FR4). Cells treated with 2- and 9-azabenz(a)anthracene showed dose-dependent increased survival. After continued subculturing, the surviving cells from 2- and 9-azabenz(a)anthracene-treated cultures displayed morphological transformation and ability to grow in semi-solid medium. Mock-treated controls and I-azabenz(a)anthracene-treated cultures did not show either of these properties. These data suggest that certain azabenz(a)anthracenes are potential carcinogens.
Subject(s)
Aza Compounds/toxicity , Benz(a)Anthracenes/toxicity , Carcinogens , Cell Transformation, Neoplastic/drug effects , 4-Nitroquinoline-1-oxide , 9,10-Dimethyl-1,2-benzanthracene , Animals , Cell Survival/drug effects , Cells, Cultured , RatsABSTRACT
The mutagenic activity of 7 aza-aromatic hydrocarbons, which are suspected of being environmental pollutants, was assessed using the Salmonella assay. The compounds tested were: 1-azachrysene, 2-azachrysene, 4-azachrysene, 1-azabenz[a]anthracene, 2-azabenz[a]anthracene, 9-azabenz[a]anthracene, and 12-benzo[a]pyrene. None of the compounds was mutagenic in the absence of S9, but all were mutagenic in the presence of S9.
