Increased mutagenicity of some nitroimidazoles by non-mutagenic nitrotoluene on Klebsiella pneumoniae (fluctuation test).

In the fluctuation test the mutation frequency of Klebsiella pneumoniae by the 5-nitroimidazoles panidazole and dimetridazole was increased by adding the non-mutagenic substances 4-nitrotoluene or toluene-4-sulfonamide. This effect was not found with 1-methyl-5-nitroimidazole, metronidazole, ronidazole, nimorazole and 1-methyl-2-hydroxymethyl-5-nitroimidazole. It is suggested that the molecules of panidazole or dimetridazole form some association, which is destroyed by 4-nitrotoluene or toluene-4-sulfonamide, thus increasing the concentration of mutagenic particles.

Mutagenic activity of acrylamide in eukaryotic systems but not in bacteria.

The vinyl monomer acrylamide (AA) was studied for its activity in a range of genotoxicity tests, including the Salmonella/microsome test, the fluctuation test using Klebsiella pneumoniae, the test for gene mutations at the TK and HPRT loci in L5178Y mouse lymphoma cells, tests for chromosomal aberrations and SCEs in V79 Chinese hamster cells, the sex-linked recessive lethal (SLRL) and somatic mutation and recombination (SMART) assays in Drosophila melanogaster and the mouse bone marrow micronucleus assay. AA showed genotoxic activity in most systems. The bacterial tests did not respond, in compliance with literature data; also in the Drosophila SLRL test, no significant increase in mutation rate was observed.

The capacity of some nitro- and amino-heterocyclic sulfur compounds to induce base-pair substitutions.

The capacity of 27 heterocyclic sulfur compounds to induce base-pair substitutions was investigated with Klebsiella pneumoniae ur- pro- and Salmonella typhimurium TA100 as test organisms. Among the compounds tested, all sulfur compounds with nitro groups and some thiazoles with an amino group were mutagenic. Among the nitrothiazoles, the most potent mutagen was niridazole, followed by 2-acetamido-5-nitrothiazole, 2-bromo-5-nitrothiazole, N-(5-nitrothiazol-2-yl)benzamide, and 2-amino-5-nitrothiazole. Of the nitrothiophenes, 2-nitrothiophene was more mutagenic than 3-nitrothiophene and 2,4-dinitrothiophene. 4-Nitroisothiazole was also mutagenic. Of the aminothiazoles, 2-amino-5-bromothiazole and 2-amino-5-chlorothiazole were mutagenic to both test organisms. With 2-amino-5-(p-nitrophenylsulfonyl)thiazole, a mutagenic action was only found with Salmonella typhimurium TA100, whereas 2-aminothiazole and 2-amino-4-methylthiazole were only mutagenic with Klebsiella pneumoniae. With the other 13 compounds, no mutagenic activity was observed. Of the coccidiostatics, 2-acetamido-5-nitrothiazole was also mutagenic on Escherichia coli K12 and Saccharomyces cerevisiae D4 but non-mutagenic on Salmonella typhimurium TA1530, TA1535, TA1537 and TA98, while 2-amino-5-nitrothiazole was mutagenic on Escherichia coli K12, Salmonella typhimurium TA1530, TA1535 and TA98, and non-mutagenic on strain TA1537 and on Saccharomyces cerevisiae D4.

Are econazole, miconazole and clotrimazole mutagenic to bacteria?

The fungistatic drugs econazole, miconazole and clotrimazole were investigated as to mutagenic properties in the fluctuation test with Klebsiella pneumoniae and Escherichia coli K12 as test organisms and in the plate-incorporation test, with and without metabolic activation, with Salmonella typhimurium strains TA98 and TA100. No mutagenic activity of the 3 compounds on these microorganisms was found.

The mutagenic action of aliphatic epoxides.

The mutagenic action of 45 epoxides was investigates in Luria and Delbrück's fluctuation test with Klebsiella pneumoniae as test organism. In this test, 36 of the 45 epoxides appeared to be mutagenic. The mutagenicity of 1,2-epoxides decreased with increasing length of the carbon chain. The mutagenic activity of compounds with a non-terminal epoxide group appeared to be less than that of substances with a terminal one. Generally 1,2-epoxide compounds with electronegative groups were more mutagenic than 1,2-epoxypropane. Of the diepoxides, 1,2,3,4-diepoxybutane appeared to be more mutagenic than 1,2,7,8-diepoxyoctane, while the ring compounds 1,2,5,6-diepoxycyclooctane was hardly mutagenic. The ring compound 4-vinylcyclohexenedioxide, used in electron microscopy that the antibiotic fosfomycin is among the more potent mutagenic substances investigated in this study.

The mutagenic action of quindoxin, carbadox, olaquindox and some other N-oxides on bacteria and yeast.

The mutagenic action of 3 coccidiostatic chinoxaline-N-oxide derivatives, quindoxin, carbadox and olaquindox, was investigated by Luria and Delbrück's fluctuation test, with Klebsiella pneumoniae and Escherichia coli K12 as test organisms. These compounds were mutagenic at very low concentrations (2 X 10(-5)--500 X 10(-5) mmole/l). In the Ames test they showed a mutagenic action without metabolic activation with Salmonella typhimurium TA98 and TA100 at concentrations of 0.001-0.1 mmole/l in the top agar. Hence, these compounds cause both base-pair substitutions and frame-shift mutations. When Saccharomyces cerevisiae D4 was cultivated in the presence of the compounds, an increase in the mitotic gene conversions was observed. Certain other N-oxides also showed a mutagenic action in the fluctuation test. With Klebsiella pneumoniae, 4-nitroquinoline 1-oxide was mutagenic at a concentration of 0.005 mmole/l, quinoline 1-oxide at 10 mmole/l and benzofuroxan at 0.01 mmole/l. In this test no mutagenic action was found with 4-nitropyridine 1-oxide, pyridine 1-oxide or 4-picoline 1-oxide. With Salmonella typhimurium TA98 and TA100, 4-nitroquinoline 1-oxide, benzofuroxan and 4-nitropyridine 1-oxide were mutagenic, whereas quinoline 1-oxide, pyridine 1-oxide and 4-picoline 1-oxide were not. In contrast, with the fluctuation test, 4-nitroquinoline 1-oxide appeared to be more mutagenic than quindoxin, carbadox and olaquindox in the plate incorporation test.

On the mutagenic action of some enzyme immunoassay substrates.

The mutagenic action of six compounds used in ELISA, EMIT and EIA assays, was investigated by means of the fluctuation test, with Klebsiella pneumoniae as a test organism, and the Ames' plate incorporation test using Salmonella typhimurium TA 98, TA 100 and TA 1537. It appears that 2,2'-azino-di(3-ethyl-benzthiazoline sulphonic acid (6)) or ABTS exerts mutagenic action on Klebsiella pneumoniae at a concentration of 11 g/l, on Salmonella typhimurium TA 100 at a top agar concentration of 0.1 g/l, on Salmonella typhimurium TA 98 at 0.2 g/l and on Salmonella typhimurium TA 1537 at 10 g/l. With umbelliferone, mutagenic action was found only with Klebsiella pneumoniae at a concentration of 0.8 g/l or higher. With o-phenylenediamine, strong mutagenic activity was found only with strain TA 98 and metabolic activation at a top agar concentration of 0.001 g/l. With 5-aminosalicylic acid, beta-methylumbelliferone and p-nitrophenyl-phosphate, no mutagenic action was observed.

The mutagenic action of nitroimidazoles. IV. A comparison of the mutagenic action of several nitroimidazoles and some imidazoles.

The mutagenic action of 51 imidazoles was investigated. The fluctuation test of Luria and Delbrück was used, with Klebsiella pneumoniae as test organism. 8 compounds, including 5 with a weak mutagenic action in the fluctuation test, were also investigated by the Ames test in which Salmonella typhimurium TA100 was used. Of the 51 imidazoles examined, 33 were nitroimidazoles. 31 of the latter appeared to be mutagenic, whereas out of the 18 other imidazoles without a nitro group only 2 were mutagenic. Several of the substances tested for mutagenicity showed an antimicrobial activity. No direct relationship between antimicrobial action, growth inhibition and mutagenicity was established. With methyl-nitroimidazoles a relationship was found between the chemical structure and mutagenic action. However, when the nitroimidazoles had a more complex chemical structure, a relationship between this structure and mutagenicity could not be established.

The mutagenic action of nitroimidazoles. II. Tinidazole, ipronidazole, panidazole and ornidazole.

The 5-nitroimidazoles tinidazole (Fasigyn), ipronidazole (Ro-7-1554), panidazole and ornidazole (Tiberal, Ro-7-0207) in concentrations of 0.02--1 mM per liter increased the mutation frequency of Klebsiella pneumoniae. Escherichia coli K12 and Citrobacter freundii to streptomycin resistance, including streptomycin dependence, in Luria and Delbrück's fluctuation test. At low concentration (0.1 mM), the increase of the mutation frequency caused by each compound was nearly the same, i.e. 3--4 times the spontaneous mutation frequency. At higher concentrations, considerable differences between the mutagenic activities of the compounds occurred.

The mutagenic action of nitroimidazoles. II. Effects of 2-nitroimidazoles.

The 2-nitroimidazoles Ro-71051 (N-benzyl-2-nitro-1-imidazole-acetamide) and Ro-5-9963 (3(2-nitro-1-imidazolyl)-1,2-propanediol) increased the mutation rate of a Klebsiella pneumoniae mutant to streptomycin-resistance including streptomycin-dependence in Luria and Delbruck's fluctuation test in concentrations of 0.05-1 mM and 0.02-0.2 mM respectively. The 2-nitroimidazole, azomycin, (Ro-5-9129/001) failed to increase the mutation rate. The results are compared to those obtained with the 5-nitroimidazoles methronidazoles metronidazole, nimorazole and dimetridazole, which caused a degree of increase similar to Ro-7-1051 and Ro-59963.