Evidence for cytochrome P-450NF, the nifedipine oxidase, being the principal enzyme involved in the bioactivation of aflatoxins in human liver.
Evidence for cytochrome P-450NF, the nifedipine oxidase, being the principal enzyme involved in the bioactivation of aflatoxins in human liver.
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细胞色素 P-450NF（硝苯地平氧化酶）的证据是参与人肝脏中黄曲霉毒素生物活化的主要酶。
DOI：
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发表时间：
1989
影响因子：
11.1
通讯作者：
F. Guengerich
中科院分区：
文献类型：
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作者：
T. Shimada;F. Guengerich
人体肝脏的体外研究表明，参与肝癌物质黄曲霉毒素 B1 (AFB1) 生物活化为其基因毒性 2,3-环氧化物衍生物的主要催化剂是细胞色素 P-450NF (P-450NF)，这是一种先前鉴定的蛋白质，也催化硝苯地平和其他二氢吡啶、奎尼丁、大环内酯抗生素、各种类固醇和其他化合物的氧化。通过鼠伤寒沙门氏菌 TA1535/pSK1002 中的 umuC 基因表达反应监测 AFB1 的激活，以及酶重建、免疫化学抑制、反应与不同肝脏样本中 P-450NF 水平和硝苯地平氧化酶活性的相关性、7,8-苯并黄酮对活性的刺激以及醋竹桃霉素对活性的抑制，获得了证据。当测量DNA中形成的2,3-二氢-2-(N7-鸟苷基)-3-羟基黄曲霉毒素B1的水平时，获得了类似的结果。 P-450NF 或密切相关的蛋白质似乎也是参与黄曲霉毒素 G1 和杂色曲霉素激活的主要催化剂，后一种化合物在这些系统中比 AFB1 更具遗传毒性。已知多种药物和条件会影响人肝脏中 P-450NF 的水平和活性，并且可以通过非侵入性测定来估计该酶的活性。这些发现为以下假设提供了一个测试系统：特定的人类疾病状态（肝癌）与黄曲霉毒素摄入量高的人群的氧化代谢水平有关。
In vitro studies with human liver indicate that the major catalyst involved in the bioactivation of the hepato-carcinogen aflatoxin B1 (AFB1) to its genotoxic 2,3-epoxide derivative is cytochrome P-450NF (P-450NF), a previously characterized protein that also catalyzes the oxidation of nifedipine and other dihydropyridines, quinidine, macrolide antibiotics, various steroids, and other compounds. Evidence was obtained using activation of AFB1 as monitored by umuC gene expression response in Salmonella typhimurium TA1535/pSK1002 and enzyme reconstitution, immunochemical inhibition, correlation of response with levels of P-450NF and nifedipine oxidase activity in different liver samples, stimulation of activity by 7,8-benzoflavone, and inhibition of activity by troleandomycin. Similar results were obtained when levels of 2,3-dihydro-2-(N7-guanyl)-3-hydroxyaflatoxin B1 formed in DNA were measured. P-450NF or a closely related protein also appears to be the major catalyst involved in the activation of aflatoxin G1 and sterigmatocystin, the latter compound being more genotoxic than AFB1 in these systems. Several drugs and conditions are known to influence the levels and activity of P-450NF in human liver, and the activity of the enzyme can be estimated by noninvasive assays. These findings provide a test system for the hypothesis that a specific human disease state (liver cancer) is linked to the level of oxidative metabolism in populations in which aflatoxin ingestion is high.