Early detection of carcinogenic substances and modifiers in rats.
Over the past 20 years, we have been developing in vivo medium-term bioassay systems in rats for detecting carcinogenic and modifying effects of test compounds. The systems are based on the two-step hypothesis of carcinogenesis. In a liver model, male F344 rats are initially given a single dose of diethylnitrosamine (DEN, 200 mg/kg, i.p.) and starting 2 weeks later are treated with test compounds for 6 weeks and then killed, all rats being subjected to two-thirds partial hepatectomy at week 3. Carcinogenic potential is scored by comparing the numbers and areas per cm(2) 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. A positive response is defined as a significant increase in the quantitative values of GST-P-positive foci, such a negative response as no change or a decrease. The results obtained have been compared with reported Salmonella/microsome and long-term carcinogenicity test findings for the same compounds. Of the liver carcinogens, 30 out of 31 (97%) mutagenic and 29 out of 33 (88%) non-mutagenic compounds gave positive results. Carcinogens other than hepatocarcinogens gave a lower proportion of positive results (9 out of 42, 21%). This bioassay also provides information concerning inhibitory potential. The practical utility and benefits of a multi-organ medium-term experimental protocol for early detection of carcinogenic agents and modifiers acting at sites other than the liver are also discussed.
Ito
N
N
Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Japan. nito@adm.nagoya-cu.ac.jp
Imaida
K
K
Asamoto
M
M
Shirai
T
T
D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D018675:Toxicity Tests / Q000379:methods*
D002273:Carcinogens; D007527:Isoenzymes; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; C496558:Gstp1 protein, rat