DIETARY CARCINOGENS AND MAMMARY CARCINOGENESIS - INDUCTION OF RAT MAMMARY CARCINOMAS BY ADMINISTRATION OF HETEROCYCLIC AMINES IN COOKED FOODS

Grilled or fried meat and fish contain various mutagenic heterocyclic amines, and structures of at least 19 compounds have already been dete rmined. Among these, 10 have been examined for long term carcinogenici ty, all proving to be positive. 2-Amino-1-methyl-6-phenylimidazo[4,5-b ]pyridine (PhIP), for example, preferentially induced mammary adenocar cinomas in 47% of Fischer 344 female rats when supplemented into the d iet at a concentration of 400 parts per million (ppm) for 52 weeks. Mo reover, 100 ppm of PhIP for 104 weeks yielded the same incidence. PhIP in the diet for 48 weeks also induced mammary cancer in Sprague-Dawle y female rats with incidences of 72 and 25% at 200 ppm and 100 ppm. 2- Amino-3,4-dimethylimidazo[4,5-f]quinoline in the diet at 300 ppm also induced a 25% incidence of mammary adenocarcinomas within 40 weeks. An alysis of PhIP-induced rat mammary carcinomas for ras mutations by pol ymerase chain reaction-single-strand conformation polymorphism and dir ect sequencing revealed Ha-ras activation in 3 of17 carcinomas; all we re G->-A transitions at the second letter of codon 12 replacing glycin e by glutamic acid. A p53 gene mutation was also found in 1 of 10 carc inomas examined; a G-->T transversion was detected at the third letter of codon 130, with a substitution of asparagine for lysine. PhIP is t he most abundant mutagenic and carcinogenic heterocyclic amine in gril led meat, and, therefore, a role for this compound in human carcinogen esis is strongly implied.