Food-derived heterocyclic amine mutagens: variable metabolism and significance to humans

The cooking of meat has been found to generate compounds that possess extreme mutagenicity when examined in short term tests. This observation led to the isolation and identification of a family of mutagenic chemicals, all of which are heterocyclic amines. These amines are potent bacterial and eukaryotic cell mutagens, and all of those tested have been found to induce tumors in laboratory animals. Metabolic activation of the heterocyclic amines predominantly involves CYP1-mediated N-hydroxylation and then O-esterification by phase II enzymes. In contrast, carbon oxidation, glucuronidation, and sulfation reactions at sites other than the hydroxylamine yield detoxication metabolites. In humans, the activities of these pathways are known to vary between individuals and are likely to influence susceptibility to the genetic toxicity of the heterocyclic amines. Clearly, accurate determination of human exposure to the heterocyclic amines and identification of the key enzyme systems involved and their regulation will be required for rational assessment of the risk and will help devise strategies to reduce such risk.