Enhancing effect of various hepatocarcinogens on induction of preneoplastic glutathione S-transferase placental form positive foci in rats--an approach for a new medium-term bioassay system.
A large series of assays of the hepatocarcinogenic potential of 112 different compounds were carried out using a rapid bioassay system developed in this laboratory based on the two-step concept of hepatocarcinogenesis. Rats were initially given a single dose (200 mg/kg) of diethylnitrosamine (DEN) i.p. and starting 2 weeks later were treated with test compounds for 6 weeks and then killed, all rats being subjected to two-thirds partial hepatectomy (PH) at week 3. Carcinogenic potential was scored by comparing the number and area per cm2 of induced glutathione S-transferase placental form-positive (GST-P+) foci in the liver with those of the corresponding control group given DEN alone. Positive was scored for a significant increase in the value of GST-P+ foci, negative for no change or a decrease. Results were compared to reported Salmonella/microsome and long-term carcinogenicity test findings. Of the liver carcinogens, 10 out of 11 (90.9%) mutagenic, and 11 out of 13 (84.6%) non-mutagenic compounds gave positive results (mean, 87.5%). Carcinogens other than the hepatocarcinogens gave less positive results (two out of 17, 11.8%). None of the compounds reported as non-carcinogenic demonstrated positivity suggesting that the assay system does not suffer from the disadvantage of false-positive results. The protocol system also provided information concerning the inhibitory potential of compounds such as anti-oxidants. It is concluded that the present experimental protocol which requires far fewer animals and shorter duration than a long-term carcinogenicity test has practical applications for the rapid and economical screening of environmental hepatocarcinogens and their inhibitory agents.
Ito
N
N
First Department of Pathology, Nagoya City University Medical School, Japan.
Tsuda
H
H
Tatematsu
M
M
Inoue
T
T
Tagawa
Y
Y
Aoki
T
T
Uwagawa
S
S
Kagawa
M
M
Ogiso
T
T
Masui
T
T
D000818:Animals; D001681:Biological Assay; D004052:Diethylnitrosamine; D004790:Enzyme Induction; D005982:Glutathione Transferase / Q000096:biosynthesis*; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000201:enzymology; D008297:Male; D009152:Mutagenicity Tests; D010920:Placenta / Q000201:enzymology*; D011230:Precancerous Conditions / Q000139:chemically induced* / Q000201:enzymology; D051381:Rats; D011916:Rats, Inbred F344
D004052:Diethylnitrosamine; D005982:Glutathione Transferase