Effect of dipyridoimidazole pretreatment on mutagen activation in rats.

Rats were pretreated with a single oral dose of different mutagenic fractions obtained from glutamic acid pyrolysate: Glu-P-2 (2-amino-dipyrido[1,2-a:3',2'-d]imidazole), Glu-P-3 (3-amino-4,6-dimethyldipyrido[1,2-a:3',2'-d]imidazole), the tar residue and a basic extract (B2). The liver S9 fractions of these animals were used to investigate the mutagenic activation of 3 promutagens (2-aminoanthracene, Glu-P-2 and Glu-P-3) in Salmonella typhimurium strain TA1538. Different factors were analyzed; influence of the structure of the compounds administered, doses, time interval between pretreatment and sacrifice and sex of the rats.

Mutation spectrum of the mutagen 3-N,N-acetoxyacetylamino-4,6-dimethyldipyrido[1,2-a:3',2'- d]imidazole in Escherichia coli.

The mutation frequency and mutation spectrum resulting from 3-N-acetylamino-4,6-dimethyldipyrido[1,2-a:3',2'-d]imidazole (AGluP3) DNA adducts using a previously developed forward mutation assay were established. AGluP3-induced mutagenesis requires the umuC gene product(s) and exhibits similar amounts of base pair substitution and frameshift mutation. Comparison between these results and those obtained with the isosteric amine 2-N-acetylaminofluorene suggests the involvement of deacetylated adduct in the molecular mechanisms of AGluP3-induced mutagenesis.

Comparison of the reactivity of B-DNA and Z-DNA with two isosteric chemical carcinogens: 2-N,N-acetoxyacetylaminofluorene and 3-N,N-acetoxyacetylamino-4,6-dimethyldipyrido-[1,2-a:3',2' -d] imidazole.

The reactivity of nucleic acids in various conformations and two isosteric chemical carcinogens 2-N,N-acetoxyacetylaminofluorene (N-AcO-AAF) and 3-N,N-acetoxyacetylamino-4,6-dimethyldipyrido [1,2-a:3',2'-d] imidazole (N-AcO-AGlu-P-3) have been studied. Both carcinogens bind covalently to poly(dG-dC).poly(dG-dC) (B form) and to poly(dG-br5C).

In vitro enzymatic methylation of DNA modified with the mutagenic amine: 3-N,N-acetoxyacetylamino-4,6-dimethyldipyrido(1,2-a:3'2'-d )imidazole.

Both the initial velocity and the overall methylation of DNA modified by acetylamino-4,6-dimethyldipyrido(1,2-a:3',2'-d)imidazole (A-Glu-P-3) by rat liver DNA-(cytosine-5-)-methyltransferase are decreased as compared to native DNA. A-Glu-P-3 bound to guanine residues may block the movement of the enzyme along the helix. The modified DNA does not inhibit the enzymatic methylation of native DNA.

Immunological titration of 3-N-acetyl-hydroxyamino-4,6-dimethyldipyrido(1,2-a:3',2'-d) imidazole-rat liver DNA adducts.

Antibodies to N-(guanosin-8-yl)-3-N-acetylamino-4,6-dimethyldipyrido(1,2-a :3',2'-d)imidazole were elicited in rabbits by immunization with a conjugate formed between this compound and bovine serum albumin. The specificity of the antibodies was studied by radioimmunoassay. These antibodies were used to titrate the adducts formed in liver DNA of rats treated with 3-N-acetyl-hydroxyamino-4,6-dimethyldipyrido(1,2-a:3',2'-d)imidazo le,p6 a supposed metabolite of the mutagenic amine 3-amino-4,6-dimethyldipyrido(1,2-a:3',2'-d)imidazole (Glu-P-3).