Epidemiological evidence strongly suggests that diet is an important factor in the etiology of human cancer but the mechanisms underlying this association are largely unknown. Some foods contain naturally occurring mutagens whilst others acquire them because of contamination by micro-organisms. Recently, attention has focussed on the generation of mutagenic chemicals in food, particularly meat and fish, during cooking. Amongst these numerous mutagens are the heteroaromatic amines (HA's) of the carboline and imidoquinoline type. The overall purpose of this project is to conduct an in-depth study of HA's in cooked food. The data generated will help determine the relevance of these chemicals to human cancer and give a basis for suggesting changes in diet if these are deemed necessary. The specific objectives are: 1. To develop assays, based on combined gas or liquid chromatography-mass spectrometry (GC-MS or LC-MS), to measure mutagenic HA's in foods and the unchanged amines and their major metabolites in body fluids. 2. To determine the extent of absorption, the metabolic fate and the routes of excretion of HA's and their metabolites in laboratory animals. 3. To compare the metabolism of these amines by human and animal tissues in order to identify a major metabolite which may be used to determine the body burden of these compounds in subjects consuming HA's in food. 4. To confirm previous results that the enzymic activation of these amines is mediated by the cytochrome P-450 system and involves the formation of intermediate N-hydroxy derivatives. 5. To determine the fate of the mutagenic intermediates in hepatocytes from rats, dogs and man in order to identify possible excretory metabolites which may be used to assess the extent of metabolism via this pathway in vivo in animals and in man. 6. Using the information gathered in 1 - 5, to establish methods to measure the absorption and metabolic activation of HA's from food consumed by human volunteers and to identify factors which influence these parameters.
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