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4-Aminobiphenyl Downregulation of NAT2 Acetylator Genotype–Dependent N- and O-acetylation of Aromatic and Heterocyclic Amine Carcinogens in Primary Mammary Epithelial Cell Cultures from Rapid and Slow Acetylator Rats

机译:快速和慢速乙酰化大鼠原代乳腺上皮细胞培养物中NAT2乙酰化剂基因型依赖性芳香族和杂环胺致癌物的4-氨基联苯下调

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摘要

Aromatic and heterocyclic amine carcinogens present in the diet and in cigarette smoke induce breast tumors in rats. N-acetyltransferase 1 (NAT1) and N-acetyltransferase 2 (NAT2) enzymes have important roles in their metabolic activation and deactivation. Human epidemiological studies suggest that genetic polymorphisms in NAT1 and/or NAT2 modify breast cancer risk in women exposed to these carcinogens. p-Aminobenzoic acid (selective for rat NAT2) and sulfamethazine (SMZ; selective for rat NAT1) N-acetyltransferase catalytic activities were both expressed in primary cultures of rat mammary epithelial cells. PABA, 2-aminofluorene, and 4-aminobiphenyl N-acetyltransferase and N-hydroxy-2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine and N-hydroxy-2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline O-acetyltransferase activities were two- to threefold higher in mammary epithelial cell cultures from rapid than slow acetylator rats. In contrast, SMZ (a rat NAT1-selective substrate) N-acetyltransferase activity did not differ between rapid and slow acetylators. Rat mammary cells cultured in the medium supplemented 24 h with 10μM ABP showed downregulation in the N-and O-acetylation of all substrates tested except for the NAT1-selective substrate SMZ. This downregulation was comparable in rapid and slow NAT2 acetylators. These studies clearly show NAT2 acetylator genotype–dependent N- and O-acetylation of aromatic and heterocyclic amine carcinogens in rat mammary epithelial cell cultures to be subject to downregulation by the arylamine carcinogen ABP.
机译:饮食和香烟烟雾中存在的芳香族和杂环胺类致癌物会诱发大鼠乳腺肿瘤。 N-乙酰基转移酶1(NAT1)和N-乙酰基转移酶2(NAT2)酶在其代谢激活和失活中具有重要作用。人类流行病学研究表明,NAT1和/或NAT2中的遗传多态性会改变接触这些致癌物的女性患乳腺癌的风险。对氨基苯甲酸(对大鼠NAT2选择性)和磺胺二甲嘧啶(SMZ;对大鼠NAT1选择性)N-乙酰基转移酶的催化活性均在大鼠乳腺上皮细胞的原代培养物中表达。 PABA,2-氨基芴和4-氨基联苯N-乙酰基转移酶和N-羟基-2-氨基-1-甲基-6-苯基咪唑并[4,5-b]吡啶和N-羟基-2-氨基-3,8-在快速的乳腺上皮细胞培养物中,二甲基咪唑并[4,5-f]喹喔啉的O-乙酰基转移酶活性要比慢速乙酰化大鼠的快2-3倍。相反,SMZ(大鼠NAT1选择性底物)的N-乙酰基转移酶活性在快速和慢速乙酰化剂之间没有差异。在补充有10μMABP的培养基中培养24小时的大鼠乳腺细胞,除NAT1选择性底物SMZ以外,所有受测底物的N-和O-乙酰化均下调。这种下调在快速和慢速NAT2乙酰化剂中是可比的。这些研究清楚地表明,在大鼠乳腺上皮细胞培养物中,芳香族和杂环胺致癌物的NAT2乙酰化基因型依赖性N和O-乙酰化受到芳基胺致癌物ABP的下调。

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