Metabolism of carcinogenic heterocyclic and aromatic amines by recombinant human cytochrome P450 enzymes
Metabolism of carcinogenic heterocyclic and aromatic amines by recombinant human cytochrome P450 enzymes
复制标题
DOI：
10.1093/carcin/18.4.851
复制
发表时间：
1997-04-01
期刊：
影响因子：
4.7
通讯作者：
Kadlubar, FF
中科院分区：
文献类型：
--
作者：
Hammons, GJ;Milton, D;Kadlubar, FF
致癌芳香胺的N-羟基化是其代谢活化的初始步骤，动物研究表明，该反应由细胞色素P450（P450）酶P450 1A 1和P450 1A 2催化。在这项研究中，利用在大肠杆菌（和纯化）或人B-淋巴母细胞中表达的酶，重组人P450 1A 1，P450 1A 2和P450 3A 4的催化活性的N-羟基化的几种致癌芳香胺进行了测定。来自两种表达系统的P450 1A 2催化4-氨基联苯和杂环胺，2-氨基-3-甲基咪唑[4，5-f]喹啉（IQ）、2-氨基-3，8-二甲基咪唑[4，5-f]喹喔啉（MeIQx）和2-氨基-1-甲基-6-苯基咪唑[4，5-B]吡啶（PhLP）的N-羟基化，速率相似，值为1.1-7.8 nmol/min/nmol P450，相反，P450 1A 1仅催化PhIP的N-羟基化，而P450 3A 4没有观察到活性。用纯化的P450 1A 2进行的进一步动力学分析显示，在人肝微粒体中，芳胺、呋拉茶碱和氟伏沙明（P450 1A 2活性的抑制剂）的N-羟基化的K-m和V-max值相似，本研究的结果支持人P450 1A 2在芳胺代谢活化中的主要作用。
The N-hydroxylation of carcinogenic arylamines represents an initial step in their metabolic activation, Animal studies have shown that this reaction is catalyzed by the cytochrome P450 (P450) enzymes P450 1A1 and P450 1A2. In this study, utilizing enzymes expressed in Escherichia coli (and purified) or in human B-lymphoblastoid cells, the catalytic activities of recombinant human P450 1A1, P450 1A2, and P450 3A4 for N-hydroxylation of several carcinogenic arylamines were determined. P450 1A2 from both expression systems catalyzed the N-hydroxylation of 4-aminobiphenyl and the heterocyclic amines, 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,8-dimethylimidazol[4,5-f]quinoxaline (MeIQx), and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhLP), Rates were similar, with values of 1.1-7.8 nmol/min/nmol P450, In contrast, P450 1A1 catalyzed N-hydroxylation of only PhIP, and no activity was observed with P450 3A4, Further kinetic analysis with purified P450 1A2 showed similar K-m and V-max values for N-hydroxylation of the arylamines, Furafylline and fluvoxamine, inhibitors of P450 1A2 activity in human liver microsomes, were found to be inhibitory of the recombinant P450 1A2 N-hydroxylation activity, Results from this study are supportive of a major role for human P450 1A2 in the metabolic activation of arylamines.