Repair synthesis of DNA induced by the urinary N-hydroxy metabolites of carcinogenic arylamines in urothelial cells of susceptible species.
Urinary N-hydroxy metabolites of the bladder carcinogens, 2-aminofluorene and 4-aminobiphenyl, were examined for the induction of unscheduled DNA synthesis (UDS) in urothelial cells of several susceptible species. N-Hydroxy-2-aminofluorene, N-hydroxy-2-acetylaminofluorene (N-OH-AAF), N-hydroxy-4-aminobiphenyl, N-hydroxy-4-acetylaminobiphenyl, and the N-glucuronides of these two hydroxylamines induced UDS in the urothelial cells of dogs, rats, and rabbits. N-Hydroxy-2-aminonaphthalene, N-hydroxy-2-acetylaminonaphthalene, and the N-glucuronide of the hydroxylamine were not active. The induction of UDS in dog cells by N-OH-AAF or N-acetoxy-2-acetylaminofluorene, but not by N-hydroxy-2-aminofluorene, was inhibited by paraoxon. The microsomal fraction of dog urothelial cells catalyzed the binding of N-OH-AAF to transfer ribonucleic acid; the enzyme activity was completely inhibited by paraoxon, suggesting that N-deacetylase, but not N-,O-acetyltransferase, was responsible for the binding. The O-glucuronide of N-OH-AAF did not induce UDS in the urothelial cells of dogs, rats, or rabbits, nor did it bind to tRNA in the presence of dog urothelial enzymes, which suggest that N-OH-AAF is detoxified by O-glucuronidation. These results are consistent with the hypothesis that nonacetylated, N-hydroxylated metabolites play a major role in arylamine-induced bladder carcinogenesis. The importance of arylacethydroxamic acid metabolites in bladder carcinogenesis for various species may be inversely related to the rate of hepatic O-glucuronidation.
D000818:Animals; D001713:Biphenyl Compounds / Q000378:metabolism / Q000494:pharmacology / Q000652:urine; D002273:Carcinogens / Q000494:pharmacology*; D004260:DNA Repair / Q000187:drug effects*; D004261:DNA Replication / Q000187:drug effects*; D004285:Dogs; D004848:Epithelium / Q000378:metabolism; D005260:Female; D005449:Fluorenes / Q000378:metabolism / Q000494:pharmacology / Q000652:urine; D006898:Hydroxylamines / Q000378:metabolism / Q000494:pharmacology / Q000652:urine*; D007700:Kinetics; D008297:Male; D010261:Paraoxon / Q000494:pharmacology; D012343:RNA, Transfer / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D013045:Species Specificity; D013329:Structure-Activity Relationship; D001743:Urinary Bladder / Q000378:metabolism*
D001713:Biphenyl Compounds; D002273:Carcinogens; D005449:Fluorenes; D006898:Hydroxylamines; D012343:RNA, Transfer; D010261:Paraoxon