Metabolic activation of N-hydroxy-4-acetylaminobiphenyl by cultured human breast epithelial cell line MCF 10A.
Metabolism and nucleic acid binding of the mammary gland carcinogen N-hydroxy-4-acetylaminobiphenyl (N-OH-AABP) was investigated using the human mammary epithelial cell line MCF 10A. Chromatographic analysis of the ethyl acetate extract of the media from cultured MCF 10A after 24 h exposure to N-OH-AABP revealed the formation of two metabolites, 4-aminobiphenyl (ABP) and 4-acetylaminobiphenyl (AABP). Incubation of [3H]N-OH-AABP with calf thymus DNA in the presence of the cytosols or microsomes revealed a binding of 0.21 and 2.36 nmol/mg DNA/mg protein respectively. In contrast to cytosol-mediated binding, the microsome-mediated binding of [3H]N-OH-AABP to DNA was inhibited by paraoxon. Furthermore, exogenous addition of non-labelled N-hydroxy-4-aminobiphenyl (N-OH-ABP) to the incubation mixture blocked the binding of [3H]N-OH-AABP to DNA, suggesting that the metabolic activation process involves inter-molecular transacetylation. Cytosols from MCF 10A also catalyzed acetyl coenzyme A (AcCoA)-dependent binding of [3H]N-OH-ABP to DNA; the amount of binding was 0.51 nmol/mg DNA/mg protein. HPLC of the DNA hydrolysate obtained after incubation of [3H]N-OH-AABP and [3H]N-OH-ABP with the MCF 10A microsomes and cytosols showed N-(deoxyguanosin-8-yl)-4-aminobiphenyl (dG-ABP) as the primary adduct, based on the mobility of the radioactive peak in comparison with the synthetic standard. 32P-postlabeling of adducted DNA obtained on incubation with N-OH-ABP or N-OH-AABP showed similar adduct profiles, with the major adduct corresponding with the bisphospho derivative of dG-ABP and a minor adduct corresponding with N-(deoxyadenosin-8-yl)-4-aminobiphenyl (dA-ABP). Additionally, the cellular DNA isolated from MCF 10A following exposure to N-OH-AABP also revealed a major spot corresponding with the dG-ABP derivative. These results suggest that the mammary gland carcinogen N-OH-AABP is activated to reactive electrophilic species in the target human mammary tissues by acetyl transferase(s) enzyme systems.[1]References
- Metabolic activation of N-hydroxy-4-acetylaminobiphenyl by cultured human breast epithelial cell line MCF 10A. Swaminathan, S., Frederickson, S.M., Hatcher, J.F. Carcinogenesis (1994) [Pubmed]
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