Metabolic activation of N-hydroxy-4-acetylaminobiphenyl by cultured human breast epithelial cell line MCF 10A.
Metabolic activation of N-hydroxy-4-acetylaminobiphenyl by cultured human breast epithelial cell line MCF 10A.
复制标题
培养的人乳腺上皮细胞系 MCF 10A 对 N-羟基-4-乙酰氨基联苯的代谢激活。
DOI：
10.1093/carcin/15.4.611
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发表时间：
1994
期刊：
影响因子：
4.7
通讯作者：
Hatcher,JF
中科院分区：
文献类型：
--
作者：
Swaminathan,S;Frederickson,SM;Hatcher,JF
Metabolism and nucleic acid binding of the mammary gland carcinogenN-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 1OA after 24 h exposure to N-OH-AABP revealed the formation of two metabolites, 4-aminobiphenyl (ABP) and 4-acetylamlnobi- phenyl (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 showedN-(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-postlabelllng 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 withN-(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.
