Dependence on exogenous metabolic activation for induction of unscheduled DNA synthesis in Syrian hamster embryo cells by diethylstilbestrol and related compounds.
Dependence on exogenous metabolic activation for induction of unscheduled DNA synthesis in Syrian hamster embryo cells by diethylstilbestrol and related compounds.
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己烯雌酚和相关化合物对叙利亚仓鼠胚胎细胞中非计划 DNA 合成的诱导依赖于外源代谢激活。
DOI：
10.2307/3577694
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发表时间：
1984
期刊：
影响因子：
11.2
通讯作者：
J. Barrett
中科院分区：
文献类型：
--
作者：
T. Tsutsui;G. Degen;D. Schiffmann;A. Wong;H. Maizumi;J. Mclachlan;J. Barrett
在没有任何可测量的基因突变诱导的情况下，己烯雌酚 (DES) 在体外诱导叙利亚仓鼠胚胎细胞的形态和肿瘤转化，这与许多其他测定中 DES 缺乏遗传毒性是一致的。然而，已经发表了一些关于 DES 在某些系统中具有基因毒性活性的报告。为了了解这些差异，我们研究了 DES 是否在导致细胞转化的条件下诱导叙利亚仓鼠胚胎细胞中的非计划 DNA 合成 (UDS)，并检查了外源代谢激活系统对 DES 诱导的 UDS 的作用。 DES 在 1 至 10 微克/毫升的浓度范围内，未能在细胞中诱导任何可检测到的 UDS，而其他已知的转化剂，包括紫外线照射（6 至 24 焦耳/平方米）、苯并（a）芘（0.1 至 1.0 微克/毫升）和黄曲霉毒素 B1（10 至 100 微克/毫升），可诱导显着水平的 UDS。相比之下，添加 Aroclor 诱导的大鼠肝脏线粒体后上清液部分和其他用于外源代谢激活的辅助因子后，DES（1 至 10 微克/ml）以剂量依赖性方式诱导 UDS。为了探究 UDS 诱导的这种改变的基础，检查了 DES 的结构类似物和代谢物诱导 UDS 的能力。在没有外源激活的情况下，在细胞存在下检测到的唯一 DES 氧化代谢物是顺式，顺式二烯雌酚，其本身不会诱导 UDS。在存在外源激活的情况下，顺式，顺式二烯雌酚及其反式，反式异构体诱导UDS，但程度不比DES更大。随着外源代谢系统的添加，观察到 DES 向顺式，顺式二烯雌酚和 DES 或二烯雌酚的其他极性衍生物（可能是羟基化衍生物）的代谢增加。在外源代谢激活下，四氟-DES和己雌酚过氧化代谢为醌和苯氧自由基中间体的能力不同，均诱导UDS，尽管10微克/ml的四氟二乙基己烯雌酚刺激更高水平的UDS。在没有外源代谢激活的情况下，所检查的 DES 相关化合物在 UDS 测定中均不具有活性，但所有化合物都可能通过过氧化物酶介导的反应形成苯氧自由基中间体。可以进一步氧化成醌的化合物在诱导UDS方面最活跃。这些结果与这种过氧化物酶介导的途径在 UDS 的诱导中很重要的假设是一致的，尽管次级代谢产物也可能参与其中。（摘要截断为 400 字）
Diethylstilbestrol (DES) induces morphological and neoplastic transformation of Syrian hamster embryo cells in vitro in the absence of any measurable induction of gene mutations, which is consistent with the lack of genotoxicity of DES in a number of other assays. However, a few reports of a genotoxic activity of DES in certain systems have been published. In order to understand these differences, we have investigated whether DES induces unscheduled DNA synthesis (UDS) in Syrian hamster embryo cells under the conditions which result in cell transformation and have examined the role of an exogenous metabolic activation system on DES-induced UDS. DES, over a concentration range of 1 to 10 micrograms/ml, failed to induce any detectable UDS in the cells, while other known transforming agents, including UV irradiation (6 to 24 J/sq m), benzo(a)pyrene (0.1 to 1.0 micrograms/ml), and aflatoxin B1 (10 to 100 micrograms/ml), induced significant levels of UDS. In contrast, UDS was induced in a dose-dependent manner by DES (1 to 10 micrograms/ml) after addition of an Aroclor-induced rat liver postmitochondrial supernatant fraction and other cofactors for exogenous metabolic activation. In order to probe the basis for this alteration in UDS induction, the ability of structural analogues and metabolites of DES to induce UDS was examined. In the absence of exogenous activation, the only oxidative metabolite of DES detected in the presence of the cells was cis,cis-dienestrol, which did not induce UDS by itself. In the presence of exogenous activation, cis,cis-dienestrol and its trans,trans-isomer induced UDS but not to a greater extent than DES. With the addition of the exogenous metabolizing system, increased metabolism of DES to cis,cis-dienestrol and additional polar derivatives of DES or dienestrol, possibly hydroxylated derivatives, were observed. With exogenous metabolic activation, tetrafluoro-DES and hexestrol, which differ in their ability to be peroxidatively metabolized to quinone and phenoxyradical intermediates, both induced UDS, although tetrafluorodiethylstilbestrol at 10 micrograms/ml stimulated a higher level of UDS. None of the DES-related compounds examined was active in the UDS assay without exogenous metabolic activation, but all of the compounds can potentially form phenoxyradical intermediates by a peroxidase-mediated reaction. The compounds which can be further oxidized to a quinone were most active in inducing UDS. These results are consistent with the hypothesis that this peroxidase-mediated pathway is important in the induction of UDS, although secondary metabolites may also be involved.(ABSTRACT TRUNCATED AT 400 WORDS)
对培养的肝细胞中计划外的 DNA 合成进行化学定量，作为快速筛选潜在化学致癌物的分析方法。
影响因子：
11.2
作者：
Althaus,FR;Lawrence,SD;Sattler,GL;Longfellow,DG;Pitot,HC
通讯作者：
Pitot,HC
己烯雌酚在孕妇和绝经前妇女的淋巴细胞中增加对姐妹染色单体交换的诱导。
影响因子：
11.2
作者：
Hill,A;Wolff,S
通讯作者：
Wolff,S