Organ specific acute toxicity of the carcinogen trans-4-acetylaminostilbene is not correlated with macromolecular binding.
trans-4-Acetylaminostilbene (trans-AAS) is acutely toxic in rats and lesions are produced specifically in the glandular stomach. Toxicity is slightly increased by pretreating the animals with phenobarbital (PB) and is completely prevented by pretreatment with methylcholanthrene (MC). The prostaglandin inhibitors, indomethacin and acetyl salicylic acid, do not reduce toxicity. The high efficiency of MC suggested that toxicity is caused by reactive metabolites. trans-[3H]-AAS was administered orally to untreated and to PB- or MC-pretreated female Wistar rats and target doses in different tissues were measured by means of covalent binding to proteins, RNA and DNA. Macromolecular binding in the target tissue of poisoned animals was significantly lower than in liver and kidney and comparable to other non-target tissues. Pretreatment with MC lowered macromolecular binding in all extrahepatic tissues but not in liver. These findings are not in line with tissue specific metabolic activation. The only unique property of the target tissue, glandular stomach, that we observed was a particular affinity for the systemically available parent compound. In the early phase of poisoning, tissue concentrations were exceedingly high and the stomach function was impaired.
D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D002273:Carcinogens; D016861:Cyclooxygenase Inhibitors; D004247:DNA / Q000378:metabolism; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism; D007408:Intestinal Absorption; D008099:Liver / Q000378:metabolism; D008748:Methylcholanthrene / Q000494:pharmacology; D009928:Organ Specificity; D011485:Protein Binding; D012313:RNA / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013267:Stilbenes / Q000378:metabolism / Q000633:toxicity*
D001798:Blood Proteins; D002273:Carcinogens; D016861:Cyclooxygenase Inhibitors; D013267:Stilbenes; C028520:4-acetylaminostilbene; D008748:Methylcholanthrene; D012313:RNA; D004247:DNA