Enhancement of GST-P positive liver cell foci development by combined treatment of rats with five heterocyclic amines at low doses

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Abstract
Potential synergism between five heterocyclic amines at low doses was evaluated in a medium-term liver bioassay system for carcinogens. F3-44 male rats were given a single i.p. injection of diethylnitrosamine (DEN, 200 mg/kg) and the received test compund(s) in their diet for 6 weeks begining 2 weeks later. Contyrol groups received DEN or test compund(s) alone. All rats were subjected to two-thirds partial hepatectomy at week 3 and killed at week 8. Coompounds tested and reported positive were 3-amino-1, 4-dimethyl-5H-pyrido [4,3-b]indole (Trp-P-1, 150 p.p.m.), 2-aminodipyrido[1,2-a: 3′,2′-d]imidazole (glu-P-2, 500 p.p.m.), 2-amino-3methylimidazo[4,5-f]quinoline (MeIQ, 300 p.p.m.), 2-amino-3,8-dimethylimidazo[4,5-f]quinocxaline (MeIQx, 400 p.p.m .). Groups were giveneach chemical at the carcinogenic dose, or 1/5;or 1/25 of this . Other groups received the five chemicals in combination, each at the 1/5;or 1/25 levels. Enhancing activity was assessed by quantitative analysis of glutathione S-transferase placental form (GST-P) positive foci, the numbers being significantly increaed with all chemicals at the highest dose. Trp-P-1, IQ and MeIQ also exerted positive influence even at the 1/5 dose level. Similar results were obtained regarding areas of foci at the highest dose levels, with exception of Glu-P-2. An increase was also observed for MeIQ at the the 1/5 dose. Additive or synergistic effects between the chemicals were evident in the groups given the five chemicals together at bothkthe 1/5 and 1/25 dose groups. Thus, carcinogenicitywas predicted for all five heterocyclic amines tested in dose-dependent manner inthe present system of 8 weeks duration, synergistic effect being apparent especially at the low dose level.

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