title: Induction of thioguanine-resistant mutations in human uroepithelial cells by 4-aminobiphenyl and its N-hydroxy derivatives.
abstract: The mutagenic potentials of the human bladder carcinogen 4-amino-biphenyl (ABP) and three of its proximate carcinogenic metabolites, N-hydroxy-4-aminobiphenyl (N-OH-ABP), N-hydroxy-4-acetylaminobiphenyl (N-OH-AABP) and N-acetoxy-4-acetylaminobiphenyl (N-OAc-AABP) were tested on a prime human target cell type for carcinogenesis, human uroepithelial cells (HUC). SV-HUC (PC), a near diploid, clonally derived, nontumorigenic SV40-immortalized human uroepithelial cell line that is transformable to tumorigenicity after exposure to ABP and its metabolites, was used for quantitative mutation assays. The end point used was the induction of mutations in the hypoxanthine-guanine phosphoribosyltransferase (HGPRT) locus, selected using 6-thioguanine resistance (TGr). A single, 24-h exposure of SV-HUC to ABP, N-OH-ABP, N-OH-AABP, or N-OAc-AABP caused a statistically significant, dose-dependent increase in mutation frequency resulting in a 2-30-fold increase in the number of TGr mutants in carcinogen-exposed groups compared to untreated controls. These chemicals were similarly mutagenic towards MC-T11, an SV-HUC-derived low grade tumor cell line that was also shown to be responsive to transformation (in a separate study) by ABP, N-OH-ABP, or N-OH-AABP as judged by the generation of higher grade tumors. In contrast, the mutagenic potencies of ABP and N-OH-ABP were lower when tested on a subclone of SV-HUC (BC) that is refractory to transformation by these chemicals. Thus, these data support a model of transformation in which ABP as well as its metabolites contribute to tumorigenic transformation and neoplastic progression of HUC by inducing mutations in susceptible target cell genes.
authors.affiliation: Department of Human Oncology and Clinical Cancer Center, University of Wisconsin, Madison 53792.
authors.forename: E A
authors.initials: EA
authors.lastname: Bookland
authors.forename: C A
authors.initials: CA
authors.lastname: Reznikoff
authors.forename: M
authors.initials: M
authors.lastname: Lindstrom
authors.forename: S
authors.initials: S
authors.lastname: Swaminathan
mesh_terms: D000611:Aminobiphenyl Compounds / Q000378:metabolism / Q000633:toxicity*; D002461:Cell Line, Transformed; D004121:Dimethyl Sulfoxide; D004351:Drug Resistance; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000187:drug effects* / Q000235:genetics; D008769:Methylnitronitrosoguanidine; D009154:Mutation; D013539:Simian virus 40; D013866:Thioguanine; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced / Q000201:enzymology
chemical_list: D000611:Aminobiphenyl Compounds; D008769:Methylnitronitrosoguanidine; C006757:4-biphenylamine; C022916:N-acetoxy-4-acetylaminobiphenyl; C014593:N-hydroxy-4-aminobiphenyl; D007041:Hypoxanthine Phosphoribosyltransferase; D013866:Thioguanine; D004121:Dimethyl Sulfoxide