Andree Bugaut

Structure—activity relationship within a series of m-diaminobenzene derivatives

We investigated the mutagenicity of m-diaminobenzene (m-phenylenediamine) and four 2,4-diaminoalkylbenzenes (methyl, ethyl, isopropyl and n-butyl) in Salmonella typhimurium strains TA100, TA1538 and TA98 in the absence and presence of S9 induced by Acoclor 1254. m-Diaminobenzene was the most active mutagen, followed by 2,4-diaminotoluene and 2,4-diaminoethylbenzene, resp. Negative response was observed for both 2,4-diaminoisopropylbenzene and 2,4-diamino-n-butylbenzene. Thus, depending on the size of the substituting alkyl group at the C1 position of 2,4-diaminoalkylbenzene, a decline and loss of mutagenic activity was observed.

Structure-activity relationships within a series of 2,4-diaminoalkoxybenzene compounds

Six 2,4-diaminoalkoxybenzenes were examined for their ability to induce mutation in Salmonella typhimurium. Each compound was tested at 8 concentrations in 5 strains. The mutagenicity was influenced by the size of the alkoxy group substituted at the C1 position of 2,4-diaminobenzene. When S9 induced by Aroclor 1254 was present, 2,4-diaminoanisole (the methoxy derivative) exhibited the highest mutagenic activity. The compounds 2,4-diaminoethoxybenzene, 2,4-diaminoisopropoxybenzene and and 2,4-diamino-n-propoxybenzene were also mutagenic, but were distinctly less active than 2,4-diaminoanisole. With the compounds 2,4-diaminophenoxyethanol and 2,4-diamino-n-butoxybenzene, the increases in numbers of revertant colonies above control levels were slight or absent. The mutagenicity of 2,4-diaminoalkoxybenzenes was detected in strains TA98, TA1538 and in some cases TA1537. None of the compounds was active in strain TA1535. The relative response of the various strains suggests that 2,4-diaminoalkoxybenzenes induce frameshift mutations but not base-pair substitutions. None of the compounds was active without metabolic activation. In addition to conducting the standard plate test, we tested the urine of rats exposed to 2,4-diaminophenoxyethanol and 2,4-diaminoanisole for mutagenicity in Salmonella typhimurium. The rats were exposed by topical application, oral administration or intraperitoneal injection. The results were positive for 2,4-diaminoanisole and negative for 2,4-diaminophenoxyethanol.

Studies on the mutagenicity of p-phenylenediamine in Salmonella typhimurium. Presence of PCB's in rat-liver microsomal fraction induced by Aroclor.

The mutagenicity of fresh solutions of p-phenylenediamine (PPD) and Aroclor 1254 was investigated. The histidine-requiring strains of Salmonella typhimurium were used in the absence and presence of uninduced and/or Aroclor-induced rat-liver homogenate. The presence of polychlorinated biphenyls (PCBs) was also examined by chromatographic methods in Aroclor-induced rat-liver homogenate. In the absence of metabolic activation, as well as in the presence of uninduced rat-liver homogenate, PPD was not mutagenic in the strains used. In the presence of Aroclor-induced S9 a twofold increase (or less) was observed in the number of revertant colonies over those of the controls in TA1538 and TA98. There was no increase in the number of revertant colonies over those of the controls when PPD was dissolved in NH4OH solution and the solution mixed with H2O2 before the addition of S9 mix. Aroclor 1254 was not mutagenic in TA1538 or TA98. However, the presence of PCBs in Aroclor-induced rat-liver homogenate (induced S9) was identified by gas-liquid chromatography (GLC), high-performance liquid chromatography (HPLC) and gas--liquid chromatography/mass spectrometry (GC/MS).

Mutagenicity of aminonitrophenol compounds in Salmonella typhimurium: a study of structural‐activity relationships

In our studies of structure‐activity relationships, four aminonitrophenol isomers and eleven derivatives of 3‐amino‐4‐nitrophenol and 4‐amino‐3‐nitrophenol were tested for their ability to induce mutations in Salmonella typhimurium strains TA1535, TA100, TA1537, TA1538 and TA98. In the presence of an Aroclor‐1254‐induced rat‐liver microsomal activation system (S9mix), 4‐N‐β‐hydroxyethylamino‐3‐nitroanisole and (4‐amino‐3‐nitro) phenoxyethanol were mutagenic in several of these strains. The compounds 3‐amino‐4‐nitrophenol, 3‐N‐methylamino‐4‐nitrophenol, 3‐N‐β‐hydroxyethylamino‐4‐nitrophenol, 3‐amino‐4‐nitroanisole, 3‐N‐methylamino‐4‐nitroanisole, 3‐N‐β‐hydroxyethylamino‐4‐nitroanisole, (3‐amino‐4‐nitro)phenoxyethanol, (3‐methylamino‐4‐nitro)phenoxyethanol, (3‐N‐β‐hydroxyethylamino‐4‐nitro)phenoxyethanol, 4‐amino‐3‐nitrophenol and 4‐N‐β‐hydroxyethylamino‐3‐nitrophenol were inactive, both in the presence and in the absence of S9 mix. In contrast to the results with 3‐amino‐4‐nitrophenol and 4‐amino‐3‐nitrophenol, which were negative, the isomers 2‐amino‐4‐nitrophenol and 2‐amino‐5‐nitrophenol were found to be mutagenic. These results on mutagenic and non‐mutagenic aminonitrophenols and their derivatives suggest that the occurrence of mutagenic activity among these compounds depends on the nature of the substituent chemical groups and their position in the molecular structure of the compounds.

Relationships between the Chemical Structure and Mutagenic Activity of Monocyclic Aromatic Amines

Hundreds of compounds have now been tested for mutagenic activity in many laboratories throughout the world. Mutagenicity tests are performed to validate a variety of assay systems and to contribute to the toxicological safety evaluation of chemicals. An area of research in genetic toxicology that has important implications for the development of safe chemical products is the study of series of homologous compounds in order to relate chemical structure to genetic activity.

Studies on the mutagenicity of resorcinol and hydroxy-3-(p-amino)anilino-6,N-[(p-amino)phenol]benzoquinonemonoimine-1,4 in Salmonella typhimurium

The hair-dye coupler resorcinol and the oxidation product of p-phenylenediamine d resorcinol, hydroxy-3-(p-amino)anilino-6,N-[(p-amino)phenol]benzoquinonemonoimine-1.4, were tested for mutagenicity in the histidine-requiring mutants of Salmonella typhimurium (TA100, TA1535, TA1537, TA1538 and TA98). The investigations were carried out in the absence and presence of rat-liver homogenate induced by Aroclor 1254 and the components of the NADPH-generating system. There was no indication of mutagenic activity by these 2 compounds at any of the 8 concentrations used. The nuclear magnetic resonance spectrum of the reaction product of p-phenylenediamine and resorcinol was recorded and is in agreement with its chemical structure.

Mutagenic evaluation of the hair-dye component 2,4-diaminophenoxyethanol in Salmonella typhimurium/microsome plate test and Saccharomyces cerevisiae strains D4 and XV185-14C

The hair-dye coupler 2,4-diaminophenoxyethanol was tested for mutagenicity in the histidine-requiring mutants of Salmonella typhimurium (TA1535, TA100, TA1537, TA1538 and TA98). The tests were carried out in the absence and presence of uninduced as well as an Aroclor-1254-induced rat-liver microsomal activation system. In the absence and presence of uninduced S9 this compound was not mutagenic in all strains used. Negative results were also obtained in the presence of an Aroclor-1254-induced rat-liver microsomal activation system. The mutagenic activity of this compound was also investigated in 2 systems of yeast, the gene conversion system with strain D4 and the reversion system with strain XV185-14C. In the absence and presence of metabolic activation, no mutagenic effect was observed.