Effects of carbon tetrachloride administration on initiation of liver cell foci by the non-hepatocarcinogens N-methyl- N′-nitro- N-nitrosoguanidine (MNNG) and benzo( a)pyrene (B(a)P)

• Published in: Cancer letters 1997-09, Vol.118 (1), p.55-60
• Main Authors: Kobayashi, Kiyoshi, Mutai, Mamoru, Goto, Kazuhiro, Inada, Ken-ichi, Tsukamoto, Tetsuya, Nakanishi, Hayao, Tatematsu, Masae
• Format: Article
• Language: English
• Subjects: Animals; B(a)P; Benzo(a)pyrene - toxicity; Biological and medical sciences; Biomarkers, Tumor; Bromodeoxyuridine; Carbon Tetrachloride - toxicity; Carcinogenesis, carcinogens and anticarcinogens; CCl 4; Cell Division - drug effects; Chemical agents; Glutathione Transferase - biosynthesis; GST-P; Hepatectomy; Initiation assay; Liver Neoplasms - chemically induced; Liver Neoplasms - pathology; Liver Regeneration - drug effects; Male; Medical sciences; Methylnitronitrosoguanidine - toxicity; Mitotic Index - drug effects; MNNG; Partial hepatectomy; Precancerous Conditions - chemically induced; Precancerous Conditions - pathology; Rats; Rats, Inbred F344; Tumors
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/S0304-3835(97)00222-X

In a development trial for an initiation bioassay system, cell proliferation kinetics after partial hepatectomy (PH) or CCl 4 administration (1 ml/kg b.w., i.g.) and the effect of administration time after PH or CCl 4 treatment on liver cell foci induction by the direct and indirect non-hepatocarcinogens, N-methyl- N′-nitro- N-nitrosoguanidine (MNNG) and benzo( a)pyrene (B(a)P) were investigated. Male F344 rats were killed 12, 18, 24, 36, 48, 72 or 96 h after PH or CCl 4 treatment and liver cell proliferation was examined with the bromodeoxiuridine (BrdU) labeling method. Appreciable increase in the BrdU labeling index was observed 18–36 h after PH with a peak at 24 h, and 18–72 h following treatment with CCl 4 with a peak at 48 h. MNNG (80 mg/kg i.g.)or B(a)P (100 mg/kg i.g.) were administered to 7-week-old male F344 rats at various times after PH or CCl 4 treatment and lesion induction was assessed using the resistant hepatocyte model. MNNG caused significant numbers of glutathione S-transferase placental form (GST-P)-positive liver cell foci in rats when given 12–36 h after PH, with a peak at 24 h. In contrast, the numbers of foci induced by B(a)P were maximal with exposure at 12 h after PH. In the CCl 4 study, both MNNG and B(a)P induced significant increase in GST-P-positive liver cell foci when given 12–72 h after CCl 4 treatment, with a peak at 48 h, the results being directly in line with the changes in BrdU labeling. From these findings, it is concluded that initiation assay protocols with a CCl 4 proliferative stimulus to hepatocytes may prolong the appropriate administration period for effective detection of the initiation potential of both direct and indirect carcinogens targeting sites other than the liver.