Correlation of nucleic acid binding by metabolites of trans-4-aminostilbene derivatives with tissue specific acute toxicity and carcinogenicity in rats.

The reaction with macromolecules was determined in various tissues of female Wistar rats 24 h following a single oral administration of [3H]-trans-4-dimethylamino- and [3H]-trans-4-acetylaminostilbene. Total binding to proteins was 4-9 times greater than to nucleic acids in most tissues. Binding to RNA and DNA was very similar and greatest in liver, about 1/4 in kidney and 1/8 - 1/10 in lung, glandular stomach (target tissue for acute toxicity), bladder, mammary glands and Zymbal glands (target tissue for carcinogenicity). The target tissues, therefore, appear not to be notably exposed to reactive metabolites. The pattern of adducts was analyzed by Sephadex LH20 chromatography of RNA and DNA hydrolysates from liver, glandular stomach, lung and kidney. It was found to be very similar qualitatively. DNA-bound metabolites were very persistent in the non-target tissues liver and kidney, t 1/2 being 34 and 60 days, respectively. Some of the major adducts in liver were not eliminated at all within 4 weeks. It thus appears that aminostilbene derivatives represent examples of strong and genotoxic carcinogens for which the extent and persistence of primary DNA lesions are not correlated with the biological effect.