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首页> 外文会议>International Conference on Monitoring of Toxic Chemical and Biomarkers >Development and application of human cell lines engineered tometabolically activate structurally diverse environmental mutagens,
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Development and application of human cell lines engineered tometabolically activate structurally diverse environmental mutagens,

机译：经过工程改造以代谢激活结构多样的环境诱变剂的人类细胞系的开发和应用，

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Abstract: Cytochromes P450 are responsible for the mutagenic/carcinogenic activation of many environmental promutagens/procarcinogens. These enzymes are present at highest concentrations in liver in vivo but are markedly absent in tester organisms for most in vitro mutagenicity test systems. Two approaches have been used to supply needed metabolic activation, incorporation of an extracellular activating system, usually derived from a rodent liver and introduction of activating enzymes into the target cell. The latter approach appears to result in a more sensitive testing system because of the close proximity of the activating enzymes and the target DNA. Human cell lines have been developed which stably express human cytochromes P450 and other cDNAs which have been introduced individually or in combination. The resulting cell lines are exquisitely sensitive to exposure to promutagens and procarcinogens. Mutagenicity is measured at the hypoxanthine phosphoribosyl transferase (hprt) and thymidine kinase (tk) gene loci. The most versatile cell line, designated MCL-5, stably express five cDNAs encoding all of the human hepatic P450s known to be principally responsible for known human procarcinogen activation. The induction of mutation is observed in MCL-5 cells upon exposure to ng/ml levels of model compounds such as nitrosamines, aflatoxin B$-1$/ and benzo(a)pyrene. A lower volume mutagenicity assay has been developed for use with samples available in limited amounts. Human lymphoblast mutation assays have been used to screen for mutagenic activity sediment samples from a polluted watershed. Two sediment samples were found to have mutagenic activity to human lymphoblasts.!17
机译：摘要：细胞色素P450负责许多环境突变蛋白/致癌物的诱变/致癌活化。这些酶在体内肝脏中以最高浓度存在，但对于大多数体外诱变性测试系统而言，在测试生物中均明显缺乏。已经使用两种方法来提供所需的代谢活化，掺入通常源自啮齿动物肝脏的细胞外活化系统以及将活化酶引入靶细胞。由于活化酶和靶标DNA的紧密接近，后一种方法似乎导致了更为灵敏的测试系统。已经开发出稳定表达人细胞色素P450和其他cDNA的人细胞系，所述细胞色素P450和其他cDNA已经被单独或组合引入。所得细胞系对暴露于链霉菌素和致癌物非常敏感。在次黄嘌呤磷酸核糖基转移酶（hprt）和胸苷激酶（tk）基因位点测量致突变性。最通用的细胞系称为MCL-5，它稳定表达五个cDNA，它们编码所有已知主要负责已知人类致癌物激活的人类肝P450。暴露于ng / ml水平的模型化合物（如亚硝胺，黄曲霉毒素B $ -1 $ /和苯并（a）py）后，在MCL-5细胞中观察到突变的诱导。已经开发了一种较低体积的致突变性测定法，可用于数量有限的样品。人类淋巴母细胞突变检测已用于筛选受污染流域的诱变活性沉积物样品。发现两个沉积物样品对人淋巴母细胞具有诱变活性！17

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