Peroxyl radical-dependent epoxidation of cyclopenteno[c,d]pyrene.
Peroxyl radical-dependent epoxidation of cyclopenteno[c,d]pyrene.
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环戊烯[c,d]芘的过氧自由基依赖性环氧化。
DOI：
10.1093/carcin/11.10.1825
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发表时间：
1990
期刊：
影响因子：
4.7
通讯作者：
Ryan,MJ
中科院分区：
文献类型：
--
作者：
Reed,GA;Ryan,MJ
环戊烯并[c，d]芘（cyclopenteno[c，d]pyrene，CPP）是一种环境中普遍存在的多环芳烃，通过几种产生过氧自由基的模型体系，CPP被激活为细菌诱变剂。在这份报告中，我们提出了我们的研究结果的化学命运的CPP在这些激活系统。所采用的过氧自由基系统是微粒体前列腺素H合酶和花生四烯酸、血红素催化的脂质过氧化氢分解和亚硫酸根阴离子的自氧化。CPP代谢的稳定产物的反相HPLC分析产生了前两个系统的定性相同的配置文件。通过UV/可见光和荧光光谱分析来自这些系统的三种主要产物，并获得最丰富产物的质谱。根据这些光谱分析和色谱行为，三种产物被鉴定为3，4-二羟基-3，4-二氢-CPP和4-酮-（3 H）-CPP的顺式和反式异构体。这些产物的特性及其相对于微粒体系统和血红素系统中存在的环氧化物水解酶活性的定量分布清楚地确立了3，4-环氧-CPP是CPP的过氧自由基依赖性代谢中产生的关键中间体和可能的活性诱变剂。CPP的活化脂族双键的这种环氧化通过证明致癌的环境相关烃的直接一步活化来扩展已知的过氧自由基依赖性氧化的范围。在亚硫酸盐依赖的系统中获得了显著不同的结果。在过氧自由基系统中观察到的环氧化物衍生代谢物是非常次要的产物。相反，两个产物峰在反相HPLC上靠近溶剂前沿。这些显然是单羟基CPP磺酸盐。这类产物可以通过将亚硫酸根阴离子自由基直接加成到CPP的活化双键上或通过CPP的过氧自由基依赖性环氧化，然后通过亚硫酸盐的亲核加成来形成。这两个反应的先例已经报道了类似的苯并[a]芘衍生物。在完整的哺乳动物系统中这些自由基依赖性转化的发生尚未进行研究，但所有三个模型系统用于将CPP转化为强效细菌诱变剂的能力意味着这些途径应进一步研究。
We have reported previously that cyclopenteno[c, d]pyrene (CPP), an environmentally prevalent polycyclic aromatic hydrocarbon, is activated as a bacterial mutagen by several model systems which generate peroxyl radicals. In this report we present our findings on the chemical fate of CPP in these activating systems. The peroxyl radical systems employed are microsomal prostaglandin H synthase and arachidonic acid, the hematin-catalyzed decomposition of a lipid hydroperoxide, and the autoxidation of the sulfite anion. Reverse-phase HPLC analysis of stable products of CPP metabolism yielded qualitatively identical profiles from the first two systems. The three major products from these systems were analyzed by UV/visible and fluorescence spectroscopy, and a mass spectrum was obtained for the most abundant product. Based on these spectral analyses and on chromatographic behavior, the three products were identified as thecis- andtrans-isomers of 3,4-dihydroxy-3,4-dihydro-CPP and 4-keto-(3H)-CPP. The identities of these products and their quantitative distributions relative to the epoxide hydrolase activities present in the microsomal system and the hematin system clearly establish 3,4-epoxy-CPP as the key intermediate and probable active mutagen generated in the peroxyl radical-dependent metabolism of CPP. This epoxidation of the activated aliphatic double bond of CPP extends the known range of peroxyl radical-dependent oxygenations by demonstrating the direct, one-step activation of a carcinogenic, environmentally relevant hydrocarbon. Strikingly different results are obtained in the sulfite-dependent system. The epoxide-derived metabolites seen with the peroxyl radical systems are very minor products. Instead, two product peaks elute near the solvent front on reverse-phase HPLC. These are apparently monohydroxy-CPP sulfonates. Such products may form either by the direct addition of the sulfite anion radical to the activated double bond of CPP or by peroxyl radical-dependent epoxidation of CPP followed by nucleophilic addition of sulfite. Precedent for both of these reactions has been reported with analogous benzo[a]pyrene derivatives. The occurrence of these radical-dependent transformations in intact mammalian systems has not been investigated, but the ability of all three model systems employed to convert CPP to potent bacterial mutagens implies that these pathways should be studied further.