Modification of the carcinogenic potency of quinoline, a hepatocarcinogen, by fluorine atom substitution: evaluation of carcinogenicity by a medium-term assay.
The potent mutagen, 5-fluoroquinoline (5-FQ), and non-mutagenic 3-fluoroquinoline (3-FQ) were tested for hepatocarcinogenicity using a medium-term assay system employing quinoline, a moderately mutagenic hepatocarcinogen, as a reference. F344 male rats were given a single i.p. injection of a submanifestational dose of diethylnitrosamine (DEN, 200 mg/kg). Then, quinoline, 3-FQ, or 5-FQ at two doses (0.1%, and 0.05%) was added to their diet for a period of 6 weeks, starting from 2 weeks after the DEN injection. Control groups were administered DEN alone. All rats were subjected to a partial (two-thirds) hepatectomy at the end of week 3 and sacrificed at the end of week 8. The number and areas of GST-P (placental glutathione S-transferase)-positive foci induced in the liver increased significantly as a result of treatment with 0.1% quinoline, and this increase was dramatic with 5-FQ at both doses, whereas no increases were noted with 3-FQ at either dose. Thus, the results of the medium-term carcinogenicity assay predicted that quinoline, a hepatocarcinogen, would be deprived of carcinogenicity by fluorine atom substitution at position 3, and would conversely be endowed with a higher carcinogenic capacity by substitution at position 5. A semi-quantitative relationship was demonstrated between carcinogenic and mutagenic potencies.
Saeki
K
K
Faculty of Pharmaceutical Sciences, Nagoya City University, Tanabedori, Mizuho-ku, Japan.
Kadoi
M
M
Kawazoe
Y
Y
Futakuchi
M
M
Tiwawech
D
D
Shirai
T
T
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002273:Carcinogens / Q000633:toxicity*; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced*; D008297:Male; D009929:Organ Size / Q000187:drug effects; D011804:Quinolines / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344; D013329:Structure-Activity Relationship
D002273:Carcinogens; D011804:Quinolines; C082975:5-fluoroquinoline; C082974:3-fluoroquinoline