Detection of initiating and promoting activity of aminophenylnorharman with a five-week in vivo initiation assay

Abstract

The initiation effects of the novel heterocyclic amine, 9-(4′-aminophenyl)-9H-pyrido[3,4-b]indole (aminophenylnorharman, APNH) on carcinogenesis were investigated in an in vivo five-week assay system. A total of 65 F344 male rats, 7 weeks old, were subjected to two-thirds partial hepatectomy (PH) and administered APNH intragastrically at doses of 10, 3, 1, and 0 mg/kg body weight (b.w.) (groups 1, 2, 3, and 5, respectively) twice, at 12 and 30 h after PH. Then the rats were fed diet containing 0.015% 2-acetylaminofluorene and given a single dose of CCl4 at week 3. Group 4 received 10 mg/kg b.w. APNH without 2-AAF and CCl4 treatment. Analysis of glutathione S-transferase placental form (GST-P) positive foci in liver sections revealed areas in groups 1, 2, and 3 to be increased in a dose dependent manner to 3.43 ± 1.38, 2.18 ± 1.41, and 0.94 ± 0.51 mm2/cm2, respectively, compared with the control value (0.22 ± 0.20 in group 5) (groups 1-3 vs. group 5, P<0.001; groups 1 vs. 2, P<0.05; groups 2 vs. 3, P<0.01). The numbers of GST-P positive foci in groups 1, 2, and 3 were, 19.34 ± 7.20, 22.75 ± 8.16 and 13.61 ± 4.92 foci/cm2 and were significantly higher than in the controls (2.67 ± 1.27 in group 5). These data suggested initiation activity of APNH. Furthermore, the area of GST-P positive foci in group 4 was increased to 0.59 ± 0.31 mm2/cm2 (P<0.05 vs. group 5) indicating promoting activity of APNH for hepatotumorigenesis. In conclusion, the above results provide evidence of initiating carcinogenic potential for APNH.