Significance of metabolic activation and binding to nucleic acids of aminostilbene derivatives in vivo.
Comparison of metabolite binding of several aminostilbene-related compounds to rat liver macromolecules in vivo supported the concept that metabolic activation is a prerequisite for biologic activity. Carcinogenic trans-4-dimethylaminostilbene and trans-4-acetylaminostilbene bound more strongly to DNA than the biologically less active cis-4-acetylaminostilbene and 4-dimethylaminobibenzyl by more than ten times. Hydroxamic acid esters did not appear to be the major metabolites which ultimately reacted with nucleic acids. The primary biochemical lesions are not correlated with tissue susceptibility. Total binding of trans-4-dimethylaminostilbene metabolites to nucleic acids was highest in the liver, about one-fifth of that total amount in the kidney, less than one-fifth in the lung and glandular stomach (which is the target tissue for acute toxicity), and still less in the forestomach and Zymbal's gland, the tissue in which tumors arise after repeated administration of test compounds to female Wistar rats. In the nontarget tissues, i.e., liver and kidney, nucleic acid binding was not only initially high but also persistent. Therefore, the exposure-related, primary biochemical lesion could not be linked to the biologic lesion. Tissue-specific parameters, other than those related to metabolic activation, are proposed to determine the biologic effect.
D000818:Animals; D001632:Bibenzyls / Q000378:metabolism; D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism*; D004247:DNA / Q000378:metabolism*; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D012335:RNA, Ribosomal / Q000378:metabolism*; D051381:Rats; D013267:Stilbenes / Q000378:metabolism*
D001632:Bibenzyls; D002273:Carcinogens; D011506:Proteins; D012335:RNA, Ribosomal; D013267:Stilbenes; C007455:4-dimethylaminobibenzyl; C028520:4-acetylaminostilbene; C007466:4-dimethylaminostilbene; D004247:DNA