Correlation between clastogenicity and promotion activity in liver carcinogenesis by N-hydroxy-2-acetylaminofluorene, N-hydroxy-4'-fluoro-4-acetylaminobiphenyl and N-hydroxy-4-acetylaminobiphenyl

• Published in: Carcinogenesis (New York) 1990-02, Vol.11 (2), p.333-339
• Main Authors: van de Poll, Monique L.M., van der Hulst, Dolinda A.M., Tates, Ad D., Meerman, John H.N.
• Format: Article
• Language: English
• Subjects: 2-Acetylaminofluorene; Aminobiphenyl Compounds - metabolism; Aminobiphenyl Compounds - toxicity; Animals; Biological and medical sciences; Carcinogenesis, carcinogens and anticarcinogens; Carcinogens; Chemical agents; DNA - metabolism; Hydroxyacetylaminofluorene - metabolism; Hydroxyacetylaminofluorene - toxicity; Liver Neoplasms, Experimental - chemically induced; Male; Medical sciences; Micronuclei, Chromosome-Defective - drug effects; Mutagens; Rats; Rats, Inbred Strains; Tumors
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/11.2.333

N-Hydroxy-2-acetylaminofluorene (N-OH-AAF), N-hydroxy-4'-fluoro-4-acetylaminobiphenyl (N-OH-FAABP) and N-hydroxy-4-acetylaminobiphenyl (N-OH-AABP) were compared for their initiation and promotion activity in the rat liver using a modified Solt—Farber system. N-OH-AAF, N-OH-FAABP and N-OH-AABP showed comparable initiation capacity when administered to male Wistar rats at a dose of 30, 120 and 120 μmol/kg respectively, 24 h after a two-thirds partial hepatectomy (PH). In contrast, only N-OH-AAF was very effective as promoter when administered to rats previously initiated with diethylnitrosamine. This was evidenced by a high number of large γ-glutamyltrans-peptidase-positive (GGT+) foci occupying a high percentage (22%.) of liver volume. N-OH-FAABP was a much weaker promoter, resulting in smaller foci and lower percentage (4%.) of GGT+ liver volume. The incomplete carcinogen N-OH-AABP was totally ineffective as promoter in our model. A similar difference was seen in the clastogenicity of these carcinogens in rat liver in vivo as measured by the formation of micronuclei: N-OH-AAF was far more clastogenic than N-OH-FAABP, which in turn was more clastogenic than N-OH-AABP. We have recently shown that N-acetylated deoxyguanosine adducts are responsible for clastogenicity of N-OH-AAF and may be important for promotion. DNA adduct analysis after injection of 120 μmol/kg of tritium-labeled N-OH-FAABP or N-OH-AABP, 24 h after PH, showed that N-acetylated adducts to C8 of deoxyguanosine are also formed from these structurally related liver carcinogens. However, the formation of these adducts from N-OH-FAABP and N-OH-AABP was ∼ 8 and ∼ 5% of the formation of dG-C8-AAF after injection of 25 μmol/kg N-OH-AAF. These data show that for the structurally related liver carcinogens N-OH-AAF, N-OH-FAABP and N-OH-AABP, clastogenicity does not predict initiating efficacy but correlates with promotion activity. Possibly, N-acetylated adducts to C8 of deoxyguanosine are involved in both clastogenicity and promotion.