The tentative identification of DNA-adducts generated by trans-4-dimethylaminostilbene and trans-4-acetylaminostilbene in rats.
Tritium-labeled trans-4-dimethylaminostilbene (DAS) and trans-4-acetylaminostilbene (AAS) were administered orally to female Wistar rats. RNA and DNA were isolated from livers after 24 h and 28 days. Hydrolysates were analyzed by gel filtration and HPLC. Total binding to nucleic acids and elution profiles of hydrolysates were very similar for both aminostilbene derivatives. The large polar fraction eluting early in Sephadex LH20 chromatograms accounting for 60-80% of total DNA-bound radioactivity could not be assigned to individual base adducts and most likely is not due to incomplete hydrolysis but rather to cross-links between bases or proteins and bases. Of the total radioactivity bound to nucleic acids 6-7% in RNA and 3-5% in DNA could be tentatively identified as four isomeric, cyclic guanine adducts (predominantly (S,S)- and (R,R)-guanine-N2,beta-N3,alpha-N-acetylaminobibenzyl) by cochromatography with synthetic reference compounds. The most abundant single adduct accounting for 20-30% of RNA-bound radioactivity (fraction G in Sephadex LH20 chromatography) could not be identified. The long-term experiment revealed different persistence of DNA adducts: the polar material decreased to about 2/3, the cyclic guanine adducts (fraction d-B) to about 1/3 to 1/2 within 4 weeks, whereas one of the unidentified DNA-adducts (fraction d-E) persisted completely. AAS labeled in the acetyl group was administered in an additional experiment. The presence of the acetyl group could be demonstrated in most of the adducts, but non-acetylated adducts were found also. The ratio of non-acetylated:acetylated cyclic B-adducts in RNA was 1:2 from DAS and 1:13 from AAS, in DNA 1:3 and 1:10, respectively.
Institute of Pharmacology and Toxicology, University of Würzburg, F.R.G.
M
M
Wildschütte
R
R
Franz
H G
HG
Neumann
D000818:Animals; D002273:Carcinogens / Q000378:metabolism*; D055598:Chemical Phenomena; D002621:Chemistry; D002850:Chromatography, Gel; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D008099:Liver / Q000378:metabolism*; D012313:RNA / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013267:Stilbenes / Q000378:metabolism* / Q000633:toxicity
D002273:Carcinogens; D013267:Stilbenes; C028520:4-acetylaminostilbene; C007466:4-dimethylaminostilbene; D012313:RNA; D004247:DNA