© 1992 Oxford University Press
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Acetyl transferase-mediated metabolic activation of N-hydroxy-4-aminobiphenyl by human uroepithelial cells
Department of Human Oncology, University of Wisconsin Comprehensive Cancer Center 600 Highland Avenue. Madison, WI 53792. USA
1To whom all correspondence should be addressed
Metabolism and nucleic acid binding of N-hydroxy-4-amlnobiphenyl (N-OH-ABP), a proximate carcinogenic metabolite of the human bladder carcinogen 4-aminobiphenyl (ABP), was investigated using cultured normal human uroepithelial cells (HUC). HPLC and TLC of the ethyl acetate extract of the media from cultured HUC after 4 h exposure to N-OH-ABP revealed the formation of two major metabolites, ABP and 4-acetylaminobiphenyl (AABP), suggesting the presence of N-acetyl tranferase(s) in HUC. This was further confirmed by the formation of AABP, during the incubation of ABP with acetyl coenzyme A (AcCoA) and HUC cytosol. To test whether these enzymes also catalyze the AcCoA-dependent O-acetylation, we examined the metabolic activation of N-OH-ABP using cytosolic preparations. Cytosol from HUC catalyzed AcCoA-dependent binding of [3H]N-OH-ABP to RNA; the amount of binding was 757 pmol/mg RNA/mg protein. Binding with DNA was quantitatively similar to RNA. HPLC and TLC analyses of the enzymatic hydrolysate of [3H]N-OH-ABP-bound DNA revealed the major adduct to be N-(deoxyguanoslne-8-yl)-4-aminobiphenyl, based on mobility of the radioactivity in comparison with the authentic synthetic standard. 32P-Post-labeling analysis of the DNA from the cytosol-mediated binding of N-OH-ABP revealed four radioactive spots. In contrast, post-labeling analysis of the DNA from intact HUC exposed to N-OH-ABP showed five adducts, including two of the adducts observed with HUC cytosols, suggesting the possible involvement of additional activation pathway(s) in intact HUC. These results suggest that bloactivatlon of N-OH-ABP could occur within the HUC, the target organ for ABP, and that cytosolic acetyl transferase(s) may play a critical role in susceptibility to arylamine-induced bladder carcinogenesis.
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