title: Mutagenic activation of 4-aminobiphenyl and its N-hydroxy derivatives by microsomes from cultured human uroepithelial cells.
abstract: Activation of the human bladder carcinogen 4-aminobiphenyl (ABP) and its N-hydroxy derivatives was investigated using lysates and subcellular enzyme preparations from cultured human uroepithelial cells (HUC). Mutagenic activation was determined using Salmonella typhimurium strains TA98; TA98/1,8-DNP6, a derivative deficient in acetyl coenzyme A:N-hydroxyarylamine O-acetyltransferase (OAT); and YG1024, a derivative of TA98 with elevated OAT activity and enhanced sensitivity to mutation by N-hydroxyarylamines. Mutagenicity of ABP catalyzed by HUC microsomes was detected in YG1024 but not in the parent strain TA98. HUC microsomes also catalyzed the mutagenic activation of N-hydroxy-4-acetylaminobiphenyl (N-OH-AABP) and the relative sensitivity of the tester strains was YG1024 > TA98 > TA98/1,8-DNP6, indicating N-hydroxy-4-aminobiphenyl (N-OH-ABP) as the mutagenic intermediate. In contrast, the mutagenic activity of N-acetoxy-4-acetylaminobiphenyl incubated with HUC microsomes was approximately equal in TA98 and YG1024, and may involve N-acetoxy-4-aminobiphenyl (N-OAc-ABP) as the intermediate. High pressure liquid chromatography (HPLC) of the DNA hydrolysate obtained after incubation of [3H]N-OH-ABP with YG1024, showed N-(deoxyguanosin-8-yl)-4-aminobiphenyl (dG-ABP) as the primary adduct, based on mobility of the radioactivity in comparison with the synthetic standard. Additionally, HUC microsomes catalyzed the binding of [3H]N-OH-ABP to RNA in the presence of 4-acetylaminobiphenyl (AABP), N-OH-AABP and acetyl coenzyme A as acetyl donors, and this binding was blocked by paraoxon. The hydrolysate obtained from incubation of DNA with [3H]N-OH-ABP and HUC microsomes, with AABP as acetyl donor, revealed the formation of dG-ABP adduct.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Human Oncology, University of Wisconsin Comprehensive Cancer Center, Madison 53792.
authors.forename: J F
authors.initials: JF
authors.lastname: Hatcher
authors.forename: K P
authors.initials: KP
authors.lastname: Rao
authors.forename: S
authors.initials: S
authors.lastname: Swaminathan
mesh_terms: D000611:Aminobiphenyl Compounds / Q000378:metabolism / Q000494:pharmacology*; D001711:Biotransformation; D002478:Cells, Cultured; D003600:Cytosol / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism; D006801:Humans; D006900:Hydroxylation; D007700:Kinetics; D008861:Microsomes / Q000378:metabolism*; D009152:Mutagenicity Tests; D009153:Mutagens / Q000494:pharmacology*; D012313:RNA / Q000378:metabolism; D012486:Salmonella typhimurium / Q000187:drug effects; D014513:Ureter / Q000378:metabolism*
chemical_list: D000611:Aminobiphenyl Compounds; D009153:Mutagens; C006757:4-biphenylamine; D012313:RNA; C014593:N-hydroxy-4-aminobiphenyl; D004247:DNA