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).
In a development trial for an initiation bioassay system, cell proliferation kinetics after partial hepatectomy (PH) or CCl4 administration (1 ml/kg b.w., i.g.) and the effect of administration time after PH or CCl4 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 CCl4 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 CCl4 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 CCl4 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 CCl4 study, both MNNG and B(a)P induced significant increase in GST-P-positive liver cell foci when given 12-72 h after CCl4 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 CCl4 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.
Kobayashi
K
K
Laboratory of Pathology, Aichi Cancer Center Research Institute, Nagoya, Japan.
Mutai
M
M
Goto
K
K
Inada
K
K
Tsukamoto
T
T
Nakanishi
H
H
Tatematsu
M
M
D000818:Animals; D001564:Benzo(a)pyrene / Q000633:toxicity*; D014408:Biomarkers, Tumor; D001973:Bromodeoxyuridine; D002251:Carbon Tetrachloride / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects; D005982:Glutathione Transferase / Q000096:biosynthesis*; D006498:Hepatectomy; D008113:Liver Neoplasms / Q000139:chemically induced* / Q000473:pathology; D008115:Liver Regeneration / Q000187:drug effects; D008297:Male; D008769:Methylnitronitrosoguanidine / Q000633:toxicity*; D008940:Mitotic Index / Q000187:drug effects; D011230:Precancerous Conditions / Q000139:chemically induced* / Q000473:pathology; D051381:Rats; D011916:Rats, Inbred F344
D014408:Biomarkers, Tumor; D008769:Methylnitronitrosoguanidine; D001564:Benzo(a)pyrene; D002251:Carbon Tetrachloride; D005982:Glutathione Transferase; D001973:Bromodeoxyuridine