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Quinoline is carcinogenic to the liver in rodents, but it is not clear whether it acts by a genotoxic mechanism. We previously demonstrated that quinoline does induce gene mutation in the liver of lambda/lacZ transgenic mice. In the present report, we reveal the molecular nature of the mutations induced by quinoline in the lambda cII gene, which is also a phenotypically selectable marker in the lambda transgene. (The cII gene has 294bp, which enables much easier sequence analysis than the original lacZ gene (3kb)). The liver cII mutant frequency was nine times higher in quinoline-treated mice than in control mice. Sequence analysis revealed that quinoline induced primarily G:C to C:G transversions (25 of 34). Thus, we have confirmed that quinoline is genotoxic in its target organ, and the G:C to C:G transversion is the molecular signature of quinoline-induced mutations.

Quinoline is carcinogenic to the liver of rats and mice and mutagenic to bacterial tester strains in the presence of rat liver microsomal enzymes. The unscheduled DNA synthesis (UDS) study suggested that quinoline might be a non-genotoxic carcinogen because of the lack of UDS-inducing capacity. In order to determine whether or not cancer induction is initiated by mutagenic DNA lesions, the present study was undertaken to evaluate the mutagenicity of quinoline in an in vivo mutation assay system using the lac Z transgenic mouse (Muta Mouse). Mutation was only induced in the liver, the target organ of carcinogenesis by quinoline, but not in the other organs examined, i.e. lung, kidney and spleen. Mutant frequency in the liver was 4-fold higher than in the untreated control animals. Dimethylnitrosamine, used as a positive control, induced mutation at a frequency 5-fold higher in the liver and 3-fold higher in the spleen than in their respective control organs. It can be concluded that the genotoxicity of quinoline is responsible for its hepatocarcinogenesis, although UDS was not induced under the conditions previously reported.

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.

The present study demonstrated the metabolism of N-hydroxyurethane by cell-free preparations, i.e., 9000 X g supernatant, cytosol and microsomes, from guinea pig livers. Under anaerobic conditions, the metabolizing activities of these preparations were enhanced markedly by addition of both an NADPH- or NADH-generating system and FAD. When the 30-45% ammonium sulfate fraction from liver cytosol was combined with liver microsomes or milk xanthine oxidase, the metabolic reaction of N-hydroxyurethane proceeded to a greater extent. Thin-layer chromatographic examination showed that urethane was only a metabolite formed from N-hydroxyurethane by these preparations.

The carcinogenicity and organ specificity of TMS-MNU and neoPNU, a carbon-analogue of TMS-MNU, in rats were investigated and compared with those of MNU. Compounds were dissolved in olive oil and rats in the experimental groups received 20 weekly intragastric intubations of 10 mg/kg of MNU or equimolar amounts of TMS-MNU or neoPNU in the same manner. The experiment was terminated when the survivors were sacrificed at the 52nd week after the final administration. In the TMS-MNU and MNU groups, tumors of the forestomach were induced and the incidence was 100% in the groups of both sexes. In addition, tumors of the glandular stomach, nervous system, kidney, and lung were also observed in these groups. Neurogenic tumors were found more frequently in the MNU group than in the TMS-MNU group. The incidence of lung tumors, however, was higher in the TMS-MNU group than in the MNU group. On the other hand, in the control and neoPNU groups, no tumor was found in these organs except the lung, and all tumors observed in these two groups were histologically similar to spontaneous ones in this strain of rats. These results indicate that the carcinogenicity of N-alkyl-N-nitrosoureas is dependent on the chemical structure of their alkyl chain. The result of the present study coincides with the previous result that the species of TMS-MNU in the alkylating step is the same as that of MNU, but different from neoPNU. The difference in the organ specificity between TMS-MNU and MNU demonstrates that the organ specificity is dominantly dependent on the distribution of the chemicals, since TMS-MNU may possibly be distributed differently from MNU because of its different partition property.

Carcinogenicity and mutagenicity of 4-nitropyridine 1-oxide (4-NPO) and 7 kinds of its alkyl derivatives were tested on mice and on Salmonella typhimurium strains and Escherichia coli strains. 3-Methyl-4-NPO is the most potent carcinogen, followed by 3-ethyl-4-NPO and then 4-NPO. Mutagenicity was most potent in 3-methyl, 2,3-dimethyl, and 2,5-dimethyl derivatives, moderate in 4-NPO and 2-methyl and 2,6-dimethyl derivatives, and to a least extent in 3,5-dimethyl-4-NPO. Structure-mutagenicity relationship was discussed on the basis of molecular mechanism of the carcinogenesis of 4-nitroquinoline 1-oxide. Quantitative relationship between mutagenicity and carcinogenicity was not strictly found among the compounds examined.

The effects of a number of 4-nitroquinoline 1-oxide and 4-nitropyridine 1-oxide derivatives, with varying carcinogenic potencies, on the scission of proteins linking DNA were studied in cultured mouse fibroblasts, strain L-P-3. With twenty-two 4-nitroquinoline 1-oxide derivatives and twelve-4-nitroquinoline 1-oxide derivatives tested, an excellent correlation was found between the scission effect of each compound and its carcinogenicity. All carcinogens, whether strong or weak, showed positive results in the scission test. Strong carcinogens such as 4-nitroquinoline 1-oxide, 2-methyl-4-nitroquinoline 1-oxide, 6-methyl-4-nitroquinoline 1-oxide, 6-chloro-4-nitroquinoline 1-oxide,and 4-hydroxyaminoquinoline 1-oxide induced the scission at a low concentration of 1 x 10-5 M, while weak carcinogens such as 3-methyl-4-nitroquinoline 2-oxide, 6-n-butyl-4-nitroquinoline 1-oxide, 6-tert-butyl-4-nitroquinoline 1-oxide, 6-n-hexyl-4-nitroquinoline 1-oxide, and 6-carboxy-4-nitroquinoline 1-oxide only produced the same effect a dose levels higher than 5 x10-5 M. On the other hand, some noncarcinogenic derivatives such as 8-nitroquinoline 1-oxide, 4-hydoxy-quinoline 1-oxide, 4-aminoquinoline 1-oxide, and 6-nitroquinoline could not induce the scission, while other noncarcinogens such as 3-nitroquinoline 1-oxide, 5-nitroquinoline 1-oxide, and 5-nitroquinoline did induce scission at concentrations higher than 1 x 10-4 M. Throughout these tests the effective concentrations of active compounds were generally much lower than the concentration at which the compounds were cytotoxic. The implication of the results and the feasibility of the present method of analysis as a screening procedure for potential carcinogens and muagens are discussed.

4-(N-Hydroxy-N-methylamino)quinoline 1-oxide (N-Me-4-HAQO), the structure of which consists of a quinoline 1-oxide moiety involved in carcinongenic 4-nitroquinoline 1-oxide and an N-hydroxy-N-methylamino group involved in N-hydroxy-N-monomethylaminoazobenzene, was sythesized and proved to be potently carcinogenic in mice by its subcutaneous injection.