RESUMO
Different derivatives of dipyrido[1,2-a:2',3'-d]imidazoles have been investigated, as mutagens for Salmonella typhimurium. The nature of different substitution groups and their positions on the base ring influenced markedly the mutagenicity of these compounds. From this structure/effect relationship study, it was demonstrated that the 2 and 3 positions were of special interest. The 3-N-hydroxylated compound was the most active mutagen tested. We also observed that the frequently found frameshift mutagens were responsible for base-pair substitution. Metabolic activation by liver S9 mix increased the reversion rates of the strains tested. The SCE assays correlated poorly with the Salmonella/microsome mutagenicity test.
Assuntos
Imidazóis/farmacologia , Mutação/efeitos dos fármacos , Células Cultivadas , Humanos , Testes de Mutagenicidade , Salmonella typhimurium/efeitos dos fármacos , Troca de Cromátide Irmã/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
The conformation of synthetic or natural DNAs modified in vitro by covalent binding of N-AcO-A-Glu-P-3 was investigated by fluorescence and circular dichroism. In all cases, substitution occurs mainly on the C8 of guanine residues. In modified poly(dG-dC).poly(dG-dC) or poly(dA-dC).poly(dG-dT) in B conformation, A-Glu-P-3 residues interact strongly with the bases whereas in Z conformation these residues are largely exposed to the solvent and interact weakly with the bases. A-Glu-P-3 and N-acetyl-2-aminofluorene (AAF) residues are equally efficient to induce the B-Z transition of poly(dG-dC).poly(dG-dC) and of poly(dA-dC).poly(dG-dT). Modifications of poly(dG).poly(dC) and calf thymus DNA indicate strong interactions between A-Glu-P-3 and the bases.
Assuntos
DNA , Imidazóis , Mutagênicos , Polidesoxirribonucleotídeos , Animais , Bovinos , Dicroísmo Circular , Conformação de Ácido Nucleico , Espectrometria de Fluorescência , Termodinâmica , TimoRESUMO
Several derivatives of dipyrido[1,2-a:3',2'-d]imidazole related to protein pyrolysates have been studied for their effects on the P-450 system of hepatic parenchyma and two dependent monoxidase enzymes, zoxazolamine hydroxylase and dimethylnitrosamine-N-demethylase (DMN-d-ase). We found that the compounds can be divided into two groups. The first group consists of compounds which inhibit the production of cytochrome P-450 and zoxazolamine hydroxylase and induce the formation of DMN-d-ase; these compounds are known to be powerful mutagens. The compounds of the second group, non-mutagens or weak mutagens, have an opposite effect: they induce the biosynthesis of cytochrome P-450 and zoxazolamine hydroxylase and repress the production of DMN-d-ase. These findings are of interest since it is known that certain of the studied compounds can be found in human food.
Assuntos
Sistema Enzimático do Citocromo P-450/genética , Microssomos Hepáticos/enzimologia , Mutagênicos , Oxirredutases N-Desmetilantes/genética , Animais , Citocromo P-450 CYP2E1 , Indução Enzimática , Repressão Enzimática , Masculino , Microssomos Hepáticos/efeitos dos fármacos , Ratos , Ratos Endogâmicos , Relação Estrutura-AtividadeRESUMO
3-Amino-4,6-dimethyldipyrido[1,2-a:3',2'-d]imidazole (Glu-P-3), an analog amine of the potent genotoxic Glu-P-1 isolated from a glutamic acid pyrolysate, has been chemically synthesized. Glu-P-3 was found much more mutagenic than Glu-P-1 to S. typhimurium TA 98 and TA 100 with S-9 mix. 3-N,N-acetoxyacetylamino-4,6-dimethyldipyrido[1,2-a:3',2'-d] imidazole (N-AcO-AGlu-P-3), a possible metabolite of Glu-P-3, binds covalently to the C-8 position of guanine residues in DNA. The binding induces large conformational changes of the macromolecule.