Liver medium-term bioassay in rats for screening of carcinogens and modifying factors in hepatocarcinogenesis.
The present report describes a study of the hepatocarcinogenic potential of a second large assay series of 94 compounds carried out using the rapid bioassay system (DEN-PH model) developed in this laboratory and based on the two-step concept of hepatocarcinogenesis. Male F344 rats were initially given a single dose of diethylnitrosamine (DEN, 200 mg/kg body weight ip) and, starting 2 wk later, were treated with test compounds for 6 wk and then killed, all rats being subjected to a two-thirds partial hepatectomy at wk 3. Carcinogenic potential was scored by comparing the numbers (no./cm2) and areas (mm2/cm2) of induced glutathione S-transferase placental form (GST-P) positive foci in the livers of groups of about 15 rats with those of corresponding control groups given DEN alone. Positive was scored for a significant increase (P < 0.05) in quantitative values of GST-P positive foci, negative for no change or a decrease. Results for the 94 compounds were also compared with previously published data from Salmonella/microsome (Ames) tests and long-term carcinogenicity studies in rats and mice. Of the known liver carcinogens, 14 out of 14 (100%) mutagenic (Ames test) compounds and 10 out of 12 (83%) non-mutagenic compounds gave positive results in our DEN-PH system (mean 92%). Two hepatocarcinogenic peroxisome proliferators did not enhance the development of GST-P positive foci. Carcinogens other than hepatocarcinogens gave fewer positive results (five out of 17, 29%). One of the 13 compounds reported as non-carcinogenic, malathion, gave positive results in the DEN-PH assay, suggesting that this compound is a weak hepatocarcinogen or tumour promoter for hepatocarcinogenesis based on the two-stage hypothesis for carcinogenesis. The present study also provided information regarding the inhibitory potential of nine compounds. The practical usefulness and benefits of the DEN-PH protocol for the rapid screening of carcinogenic agents are discussed.
Hasegawa
R
R
First Department of Pathology, Nagoya City University Medical School, Japan.
Ito
N
N
D000818:Animals; D015197:Carcinogenicity Tests / Q000379:methods*; D002273:Carcinogens / Q000633:toxicity*; D004052:Diethylnitrosamine; D004790:Enzyme Induction; D005982:Glutathione Transferase / Q000096:biosynthesis; D006498:Hepatectomy; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000201:enzymology; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344
D002273:Carcinogens; D004052:Diethylnitrosamine; D005982:Glutathione Transferase