Food Mutagens: Factors That Modulate Their Metabolic Activation.

Investigations were conducted into the factors that modulate the activation of the potent food-related mutagens; the heterocyclic aromatic amines (HAAs) formed during the cooking process and the pyrolysis of amino acids in order to assess the possible human health risk from these compounds. The food constituents anthraflavic acid, ellagic acid and retinol were all found to decrease the in vitro metabolic activation of IQ to mutagens in the Ames test. Anthraflavic acid and retinol inhibited cytochrome P450I proteins and thus the cytochrome P450lA2-mediated activation of IQ, furthermore anthraflavic acid also inhibited a cytosolic activation step which potentiates microsomal-activation. Ellagic acid did not inhibit the metabolic activation of IQ and the mechanism by which it inhibits IQ mutagenesis may involve either binding to and protecting critical sites on DNA and/or by a chemical interaction with a reactive metabolite of IQ although, the latter appears unlikely. Administration of ellagic acid at a dose previously decribed as anticarcinogenic, resulted in toxicity, and bearing in mind its poor absorption characteristics it was considered to be an unlikely inhibitor of the initiation of carcinogenesis. Anthraflavic acid when administered to rats increased hepatic cytochrome P450I proteins and hence would increase the rate of production of genotoxic species from numerous chemical carcinogens in vivo. It was thus concluded that in vitro antimutagenicity studies are irrelevant as tests for anticarcinogens, unless the mechanism of action is clearly understood and shown to be operative in vivo. Retinol was the only compound tested that could possibly modulate carcinogenicity as its inhibitory effect on the activation of precarcinogens was demonstrated at near physiological concentrations. The activation of the HAAs was found to be greatly enhanced by exposure of experimental animals to environmental aromatic amine contaminants, which induce cytochrome P450I activity, showing that dietary HAA-induced carcinogenesis may be exacerbated by environmental chemicals. Similarly IQ enhanced its own activation by inducing cytochrome P450I activity, indicating that upon repeated exposure its carcinogenic potential is increased by acting as a carcinogen and a co-carcinogen. The patho-physiological condition of type I insulin-dependent diabetes was demonstrated to enhance the activation of dietary mutagens such as HAAs and nitrosamines, since diabetes could increase the levels of some forms of hepatic cytochromes P450 in particular those that activate carcinogens namely, P450I and P450IIE proteins. It is concluded that HAAs are potentially hazardous to health, particularly to individuals having high tissue levels of cytochrome P450I proteins either due to exposure to various inducing agents, genetically determined, or a patho-physiologiacal condition that is likely to confer a high level of cytochrome P450I on the individual