Mutagenic potency of food-derived heterocyclic amines

Abstract

The understanding of mutagenic potency has been primarily approached using "quantitative structure activity relationships" (QSAR). Often this method allows the prediction of mutagenic potency of the compound based on its structure. But it does not give the underlying reason why the mutagenic activities differ. We have taken a set of heterocyclic amine structures and used molecular dynamic calculations to dock these molecules into the active site of a computational model of the cytochrome P-450 1A1 enzyme. The calculated binding strength using Boltzman distribution constants was then compared to the QSAR value (HF/6-31G* optimized structures) and the Ames/Salmonella mutagenic potency. Further understanding will only come from knowing the complete set of mutagenic determinants. These include the nitrenium ion half-life, DNA adduct half-life, efficiency of repair of the adduct, and ultimately fixation of the mutation through cellular processes. For two isomers, PhIP and 3-Me-PhIP, we showed that for the 100-fold difference in the mutagenic potency a 5-fold difference can be accounted for by differences in the P450 oxidation. The other factor of 20 is not clearly understood but is downstream from the oxidation step. The application of QSAR (chemical characteristics) to biological principles related to mutagenesis is explored in this report.3

Intake of heterocyclic aromatic amines and the risk of prostate cancer in the EPIC-Heidelberg cohort

“…1 Trend tests were performed using the continuous intake of each variable. 2 Cox proportional hazards models, stratified by age.…”

“…In vitro and in vivo experiments indicate that heterocyclic aromatic amines (HCAs) are some of the most potent mutagens [1]. These compounds are formed from amino acids, creatin(in)e and sugar during cooking of fish and/or meat at high temperatures.…”

Formação de toxinas durante o processamento de alimentos e as possíveis conseqüências para o organismo humano

“…As AH ainda podem ser encontradas em resíduos de panelas e em extratos de carne. Sua formação ocorre pela pirólise de certos aminoácidos, entre os quais triptofano, lisina, ácido glutâmico e fenilalanina, ou pela reação entre creatina (também denominada creatinina) e os produtos da Reação de Maillard 42 .…”

“…As aminas heterocíclicas são metabolizadas pelo citocromo P-450 dos microssomos hepáticos em mutágenos ativos, as N-hidroxilaminas, as quais são convertidas em compostos capazes de se unir à guanina, afetando a replicação e a transcrição do DNA 42,45,46 .…”

“…Ainda há evidências de que elas afetam o sistema vascular, as glândulas salivares e de que levam à degeneração miocardial. Entretanto, é importante salientar que cada organismo reage de maneira específica, tolerando maiores ou menores doses desses compostos [42][43][44][45][46][47][48] . Para diminuir a formação desses compostos, deve-se adicionar antioxidantes naturais ou sintéticos durante a cocção, por estarem os intermediários dos radicais livres envolvidos na reação.…”