Induction of DNA repair synthesis in human urothelial cells by the N-hydroxy metabolites of carcinogenic arylamines.
Urinary N-hydroxy metabolites of carcinogenic arylamines were investigated for their abilities to induce unscheduled DNA synthesis (UDS) in human urothelial cell lines HCV 29, HU 1734, and HU 1752, and in a primary culture of human urothelial cells. N-Hydroxy-2-aminofluorene (CAS: 53-94-1; N-OH-AF), N-hydroxy-2-acetylaminofluorene (CAS: 53-95-2; N-OH-AAF), and the N-glucuronide of N-OH-AF induced UDS in HCV 29, HU 1734, and HU 1752. N-Hydroxy-4-aminobiphenyl (CAS: 6810-26-0; N-OH-ABP), N-hydroxy-4-acetylaminobiphenyl (CAS: 4463-22-3; N-OH-AABP), N-hydroxy-2-aminonaphthalene (CAS: 613-47-8; N-OH-AN), N-hydroxy-2-acetylaminonaphthalene (CAS: 2508-23-8; N-OH-AAN), and the N-glucuronide of N-OH-ABP induced UDS in HCV 29. However, the N-glucuronide of N-OH-AN did not. The O-glucuronide of N-OH-AAF induced UDS in HCV 29 only when beta-glucuronidase was present. Paraoxon inhibited the induction of UDS in HCV 29 by N-OH-AAF and N-acetoxy-2-acetylaminofluorene (CAS: 6098-44-8), but not by N-OH-AF. When examined in a primary culture of human urothelial cells, N-OH-AF, N-OH-AAF, N-OH-ABP, and N-OH-AABP were active, but N-OH-AN, N-OH-AAN, 2-aminonaphthalene (CAS: 91-59-8), 2-aminofluorene (CAS: 153-78-6;), and 4-aminobiphenyl (CAS: 92-67-1) were not. These results demonstrate that human urothelial cells are able to activate both acetylated and non-acetylated N-hydroxy metabolites of carcinogenic arylamines, and they suggest that O-glucuronidation may be a detoxification mechanism for N-arylacethydroxamic acids.
D015081:2-Naphthylamine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D000611:Aminobiphenyl Compounds / Q000378:metabolism / Q000494:pharmacology; D001345:Autoradiography; D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism*; D002460:Cell Line; D004260:DNA Repair / Q000187:drug effects*; D005449:Fluorenes / Q000378:metabolism / Q000494:pharmacology; D005965:Glucuronates / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006881:Hydroxyacetylaminofluorene / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009280:Naphthaleneacetic Acids / Q000494:pharmacology; D001743:Urinary Bladder / Q000378:metabolism*
D000611:Aminobiphenyl Compounds; D002273:Carcinogens; D005449:Fluorenes; D005965:Glucuronates; D009280:Naphthaleneacetic Acids; C012177:2-aminofluorene; C001365:N-hydroxy-4-acetylaminobiphenyl; D006881:Hydroxyacetylaminofluorene; C001368:N-hydroxy-2-aminofluorene; C014593:N-hydroxy-4-aminobiphenyl; C040882:N-hydroxy-N-2-naphthalenylacetamide; D015081:2-Naphthylamine; C019424:N-hydroxy-2-naphthylamine