Enhancement of hepatocarcinogenesis by combined administration of food-derived heterocyclic amines at low doses in the rat

Abstract

Effects of simultaneous administration of five or 10 heterocyclic amines (HCAs) at low dose levels on rat liver carcinogenesis were investigated using a medium-term bioassay protocol. Male F344 rats were initially given diethylnitrosamine (DEN, 200 mg/kg, ip) and received HCAs starting 2 wk later for 6 wk. All animals were subjected to two-thirds partial hepatectomy at wk 3 and were killed at wk 8. Five carcinogenic HCAs in the first two experiments: 3-amino-1,4-dimethyl-5 H-pyrido[4,3- b]indole, 2-aminodipyrido[1,2-a:3′,2′- d]imidazole, 2-amino-3-methylimidazo-[4,5- f]quinoline, 2-amino-3,4-dimethylimidazo[4,5- f]quinoline, 2-amino-3,8-dimethylimidazo-[4,5- f]quinoxaline in experiment 1 and 3-amino-1-methyl-5 H-pyrido[4,3- b]indole, 2-amino-6-methyl-dipyrido[1,2-a:3′,2′- d]imidazole,2-amino-3-methyl-9 H-pyrido-[2,3- b]indole, 2-amino-9 H-pyrido[2,3- b]indole, and 2-amino-l-methyl-6-phenylimidazo[4,5- b]pyridine in experiment 2] were administered together or individually in the diet at levels of 1 1 , 1 5 or 1 25 carcinogenic doses, and all 10 chemicals were given at 1 10 or 1 100 levels in experiment 3. Induction of preneoplastic glutathione S-transferase placental form (GST-P) positive foci was increased in some combination groups over the sums of effects for the individual groups at the same doses (apparent synergism). This was most obvious in the group given all 10 chemicals at the 1/10 dose levels. However, it was of interest that the values in the combined groups were generally very close to the averages of five or 10 individual results for the corresponding higher dose groups, indicating isoadditivity of HCA effects. True (strict) synergism, however, was expected for the results of groups including Ph1P and Trp-P-2 in combination, since they are non-hepatocarcinogenic but induce the key metabolic enzyme for HCAs (CYPIA2).