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Characterization of cytochrome P450-dependent and glutathione transferase activities in SV 40-immortalized uroepithelial cell lines: possible role in transformation and tumor formation.
Snawder-JE; Savage-RE Jr.; Swaminathan-S; Frederickson-SM; Reznikoff-CA
Toxicol Methods 2000 Jul; 10(3):195-201
An in vitro/in vivo transformation system has been developed as a model for bladder tumorigenesis. SV40-immortalized human uroepithelial cells are exposed to putative carcinogens and then implanted into athymic nude mice to testfortumorigenesis. Studies with 4-aminobiphenyl(4-ABP) demonstrated that one cell line, SV-HUC-PC, was sensitive to chemical-induced transformation and another line, SV-HUC-BC, was refractory. We are currently testing this system as a model to identify occupational carcinogens and develop biomarkers of exposure and effects of exposure. As part of this study, we examined P450- dependent metabolism, glutathione transferase, and the effects of chemicals on deoxyribonucleic acid(DNA)synthesis and repair in SV-HUC-PC and SV-HUCBC. Activities for CYP1A1/1A2, CYP3A, and CYP2B1/2B2 were estimated by determining o-dealkylation of ethoxy-, benzoxy-, and pentoxy-resorufin, respectively. Coumarin hydroxylase and p-nitrophenol hydroxylase were used to estimate CYP2A and CYP2E1, respectively. SV-HUC-PC microsomes had five fold greater CYP1A1/1A2 activity and two fold higher CYP3A activity than SV-HUCBC. CYP2B1/2B2 and CYP2A activities and glutathione transferase were not different between the two cell lines. DNA synthesis and repair, by BrdU incorporation, was not different between the two lines when N-methyl-N-nitroN-nitrosoguanidine (MNNG) or other reactive metabolites were tested; however, SV-HUC-PC was more sensitive to n -nitrosodimethylamine, 4-ABP, and 4,4-methylene bis (2-chloroaniline) (MOCA). The data demonstrate that, while these cells have retained form-specific P450 activities, SV-HUC-PC has greater CYP1A1/1A2 and CYP3A activities.
Cell-transformation; Tumors; In-vitro-studies; In-vivo-studies; Models; Bladder-disorders; Bladder-disease; Bladder-cancer; Tumorigenesis; Exposure-levels; Carcinogens; Biomarkers; Laboratory-animals; Animals; Animal-studies; Author Keywords: Glutathione Transferase
John E. Snawder, NIOSH, Taft Laboratories, MS-C23, 4676 Columbia Parkway, Cincinnati, OH 45226, USA
Issue of Publication
Page last reviewed: April 12, 2019
Content source: National Institute for Occupational Safety and Health Education and Information Division