Metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a tobacco-specific carcinogen, by rabbit nasal microsomes and cytochrome P450s NMa and NMb.
Metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a tobacco-specific carcinogen, by rabbit nasal microsomes and cytochrome P450s NMa and NMb.
复制标题
4-(甲基亚硝基氨基)-1-(3-吡啶基)-1-丁酮 (NNK)（一种烟草特异性致癌物）通过兔鼻微粒体和细胞色素 P450s NMa 和 NMb 的代谢。
DOI：
10.1093/carcin/13.11.2141
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发表时间：
1992
期刊：
影响因子：
4.7
通讯作者：
Yang,CS
中科院分区：
文献类型：
--
作者：
Hong,JY;Ding,X;Smith,TJ;Coon,MJ;Yang,CS
兔鼻嗅微粒体和呼吸微粒体对4-（甲基亚硝胺基）-1-（3-吡啶基）-1-丁酮（NNK）的α-羟基化反应有催化作用，其生成酮醛的比活性分别为262和136 pmol/min/mg蛋白，生成酮醇的比活性分别为318和190 pmol/min/mg蛋白。在兔嗅觉和呼吸微粒体实验中观察到NNK-N-氧化物的形成，但在大鼠鼻微粒体中未观察到。而大鼠鼻微粒体对NNK的α-羟基化有较高的催化活性。在重组体系中，兔鼻微粒体中主要组成型P450同工酶P450 NMa在酮醛和酮醇的形成中表现出高活性，表观Km值分别为15和9 μM。相比之下，兔嗅觉特异性P450 NMb催化酮醛形成的活性较低（Km= 186 μM），而对酮醇的形成没有活性。尼古丁和二烯丙基硫醚可抑制P450 NMa催化的NNK氧化。动力学研究表明，尼古丁是一种竞争性抑制剂。这些结果表明，兔鼻微粒体中的酶，特别是P450 NMa，有效地催化NNK的生物活化。
Rabbit nasal olfactory and respiratory microsomes were found to catalyze the α-hydroxylation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) with specific activities of 262 and 136 pmol/min/mg protein in the formation of keto aldehyde, and of 318 and 190 pmol/min/mg protein in the formation of keto alcohol respectively. The formation of NNK-N-oxide was observed in experiments with rabbit olfactory and respiratory microsomes, but not with rat nasal microsomes. However, the rat nasal microsomes had higher activity in catalyzing the α-hydroxylation of NNK. In a reconstituted system, rabbit P450NMa, a major constitutive P450 isozyme in nasal microsomes, displayed high activities in the formation of the keto aldehyde and the keto alcohol with apparentKmvalues of 15 and 9 μM respectively. In comparison, rabbit olfactory specific P450NMb had a low activity in catalyzing the formation of keto aldehyde (Km= 186 μM) and no activity in the formation of keto alcohol. The P450NMa-catalyzed oxidation of NNK was inhibited by nicotine and diallyl sulfide. Kinetic studies indicated that nicotine is a competitive inhibitor. These results demonstrate that enzymes in rabbit nasal microsomes, especially P450NMa, efficiently catalyze the bioactivation of NNK.