1887

Abstract

Thirty-five substituted benzimidazoles, benzotriazoles and quinoxalines were tested as growth inhibitors on three mutants of , strain W, having different purine requirements and on the ciliate . A number of the compounds, especially those with a nitro group in the benzene ring, were inhibitory. Both organisms were affected in a similar way by the compounds. Several of these analogues were tested for mutagenic activity at the purine and streptomycin loci in a purine-requiring mutant of . Only inhibitory compounds were found to be mutagenic; non-inhibitory concentrations of one analogue, 4-nitro-6-hydroxybenzimidazole (NHB), were, however, also mutagenic. No specific mutagenesis was demonstrated. NHB was found to increase the rate of mutation as determined by the papilla method. Evidence is presented which eliminates the hypothesis that selection rather than mutagenesis was involved. This analogue did not increase the frequency of mutants in non-dividing cells, and was not incorporated into bacterial DNA. The mechanism of this mutagenesis is thought to include the inhibition of enzymes concerned with DNA synthesis. DNA and RNA and their constituents, purine and pyrimidine precursors and analogues, vitamin B and other vitamins, were found to have no effect on the inhibition or mutagenesis produced by NHB. Several amino acid combinations and one non-mutagenic analogue, 4-hydroxy-6-nitrobenzotriazole, were, however, found to interfere with mutagenesis by NHB. These compounds did not affect the frequency of spontaneous mutants. The amino acid combination was effective only when present simultaneously with the mutagen and did not act by a selection mechanism. The mechanism of antimutagenesis by amino acids may involve their ability to increase the growth rate and also to modify the inhibited nucleic acid metabolism.

The mutagenesis by 5-nitroquinoxaline, a pterin analogue, was also found to be depressed by amino acids in the same purine-requiring mutant. The annulment of mutagenic activity by amino acids was strain and mutagen specific.

Twenty-five known inhibitors of nucleic acid synthesis and antagonists to inhibition were tested for mutagenic activity in five strains of . Several, including 6-mercaptopurine, were found to be mutagenic; in addition, NHB, 5-nitroquinoxaline and 5-aminouracil were mutagenic in most of the strains tested. The mutagenic activity of 5-aminouracil was not annulled by thymine, thymidine or other nucleic acid components, but the mutagenesis of 6-mercaptopurine was annulled by purine bases and by ribosides.

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1958-06-01
2022-01-19
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