Cytotoxicity and mutagenicity of polycyclic aromatic hydrocarbon o-quinones produced by dihydrodiol dehydrogenase
Cytotoxicity and mutagenicity of polycyclic aromatic hydrocarbon o-quinones produced by dihydrodiol dehydrogenase
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DOI：
10.1016/0009-2797(95)03660-1
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发表时间：
1996-01-05
影响因子：
5.1
通讯作者：
Penning, TM
中科院分区：
文献类型：
--
作者：
FlowersGeary, L;Bleczinski, W;Penning, TM
通过二氢二醇脱氢酶 (DD) 产生的八种多环芳烃 (PAH) 邻醌在 H-4-II-e（大鼠肝癌）细胞中进行了细胞毒性检查，并在 Ames 试验中检查了其致突变性。其中七种 PAH 邻醌是强效细胞毒素，对细胞存活产生的 IC50 值在 1-30 μM 范围内。根据其细胞毒性特征，PAH 邻醌被分为三类：第一组含有邻醌（例如萘-1,2-二酮和 7,12-二甲基苯并[a]蒽-3,4-二酮），会降低细胞活力和细胞毒性。生存；第二组含有邻醌（例如苯并[a]蒽-3,4-二酮和5-甲基-1,2-二酮），可降低细胞存活率，但对细胞活力没有影响；第三组含有邻醌（例如苯并[a]芘-7,8-二酮），它对细胞活力有显着影响，但对细胞存活影响很小。使用肝癌细胞悬液和大鼠肝亚细胞部分，发现邻醌优先进行酶促单电子氧化还原循环并产生超氧阴离子自由基（O-2（-））和/或邻半醌阴离子或交替自由基。降低细胞活力的邻醌会产生 O-2(-) 并导致最多的自由基形成，而那些降低细胞存活的邻醌仅产生邻半醌阴离子或交替自由基，PAH 邻醌还在鼠伤寒沙门氏菌测试菌株 TA97a、TA98、TA100、TA102 和 TA104 中作为直接作用诱变剂进行了测试。发现它们比用于每个测试菌株的测试诱变剂具有更强的诱变性，并且主要是移码诱变剂。激活系统（Aroclor 诱导的大鼠肝脏 S9 加 NADPH）的存在不会增加对氧化诱变剂（TA102 和 TA104）敏感的测试菌株中邻醌的致突变性。这些数据表明，DD 产生的 PAH 邻醌具有不同机制的细胞毒性和致突变性。细胞毒性的机制涉及活性氧和/或邻半醌阴离子或交替自由基的形成。致突变性的机制与自由基的形成无关，并且与PAH邻醌插入和共价修饰DNA的能力有关。
Eight polycyclic aromatic hydrocarbon (PAH) o-quinones that can be generated by dihydrodiol dehydrogenase (DD) were examined for their cytotoxicity in H-4-II-e (rat hepatoma) cells and for their mutagenicity in the Ames test. Seven of the PAH o-quinones were potent cytotoxins yielding IC50 values for cell survival in the range 1-30 mu M. PAH o-quinones were grouped into three classes based on their cytotoxicity profiles: group I contained o-quinones (e.g., naphthalene-1,2-dione and 7,12-dimethylbenz[a]anthracene-3,4-dione) which reduced cell viability and cell survival; group II contained o-quinones (e.g., benz[a]anthracene-3,4-dione and 5-methylchrysene-1,2-dione) which reduced cell survival but had no effect on cell viability; and group III contained o-quinones (e.g., benzo[a]pyrene-7,8-dione) which had a pronounced effect on cell viability but minimal effects on cell survival. Using hepatoma cell suspensions and rat liver subcellular fractions, it was found that o-quinones underwent preferential enzymatic one-electron redox-cycling and produced superoxide anion radical (O-2(-)) and/or o-semiquinone anion or alternant radicals. o-quinones that reduced cell viability produced O-2(-) and caused the most total free radical formation, while those that reduced cell survival produced o-semiquinone anion or alternant radicals only, PAH o-quinones were also tested as direct-acting mutagens in Salmonella typhimurium tester strains TA97a, TA98, TA100, TA102 and TA104. They were found to be more mutagenic than the test mutagens used for each tester strain, and were predominantly frameshift mutagens. The presence of an activating system (Aroclor-induced rat liver S9 plus NADPH) did not increase the mutagenicity of o-quinones in tester strains that are sensitive to oxidative mutagens (TA102 and TA104). These data suggest that PAH o-quinones produced by DD are cytotoxic and mutagenic by different mechanisms. The mechanism of cytotoxicity involves the formation Of reactive oxygen species and/or o-semiquinone anion or alternant radicals. The mechanism of mutagenicity is independent of free radical formation and is related to the ability of PAH o-quinones to intercalate and covalently modify DNA.