Metabolic activation of cyclopenteno[c,d]pyrene by peroxyl radicals.
Metabolic activation of cyclopenteno[c,d]pyrene by peroxyl radicals.
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过氧自由基对环戊烯[c,d]芘的代谢活化。
DOI：
10.1093/carcin/9.12.2291
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发表时间：
1988
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;Layton,ME;Ryan,MJ
在产生过氧自由基的体系中，已证明了环戊烯并[c，d]（CPP）转化为对鼠伤寒沙门氏菌菌株TA 98有诱变性的形式。研究的系统包括前列腺素H合酶（PHS）和花生四烯酸，15-羟基过氧-5，8，11，13-二十碳四烯酸（15-HPETE）和血红素，以及亚硫酸根离子的自氧化。在所有情况下，在10 - 100 μM碳氢化合物浓度下观察到CPP的浓度依赖性激活。CPP或单独的过氧自由基系统对试验菌株均无致突变性或毒性。过氧化氢与PHS（一种不产生过氧自由基的过氧化体系）一起使用不会激活CPP。用1，1，1-三氯丙烯-2，3-氧化物研究了CPP环氧化物的作用，在PHS/花生四烯酸体系中加入环氧化物水解酶抑制剂，诱导的回复突变体比不加抑制剂的体系增加了210%。将纯大鼠肝微粒体环氧化物水解酶加入到CPP与15-HPETE/血红素系统的孵育中，导致致突变性的浓度依赖性丧失，进一步支持环氧化物的中间性。CPP的代谢位点是环戊烯双键，其代谢产物具有明显的芘型荧光光谱。15-HPETE/血红素系统不能激活3，4-二氢环戊烯并[c，d]芘作为诱变剂，也表明了环戊烯并双键的参与。CPP是第一个被发现直接被过氧自由基系统激活的环境相关的致癌碳氢化合物，而无需通过细胞色素P-450系统预先生物转化为二醇衍生物。这些发现扩大了潜在的有毒底物的范围被认为是激活过氧化氢自由基途径。
The conversion of cyclopento[c,d] (CPP) to forms which are mutagenic toSalmonella typhimuriumstrain TA98 has been demonstrated in systems which generate peroxyl radicals. The systems examined included prostaglandin H synthase (PHS) and arachidonic acid, 15-hydroperoxy-5,8,11,13-eicosatetraenoic acid (15-HPETE) and hematin, and the autoxidation of the sulfite ion. In all cases concentration-dependent activation of CPP was observed at hydrocarbon concentrations between 10 and 100 μM. Neither CPP nor the peroxyl radical systems alone were mutagenic or toxic to the tester strain. The use of hydrogen peroxide with PHS, a peroxidative system which does not yield peroxyl radicals, does not activate CPP. The involvement of a CPP epoxide was examined using 1,1,1-trichloropropene-2,3-oxide.Addition of this epoxide hydrolase inhibitor to incubations of CPP with the PHS/arachidonic acid system resulted ina 210% increase in induced revertants relative to the system in the absence of the inhibitor. The addition of pure rat liver microsomal epoxide hydrolase to incubations of CPP with the 15-HPETE/hematin system resulted in a concentration-dependent loss of mutagenicity, further supporting the intermediacy of an epoxide. The site of metabolism of CPP isthe cyclopenteno double bond based on the formation of products which display distinct pyrene-type fluorescence spectra. The involvement of the cyclopenteno double bond also is shown by the inability of the 15-HPETE/hematin system to activate 3,4-dihydrocyclopenteno[c,d]pyrene as a mutagen. CPP is the first environmentally-relevant carcinogenic hydrocarbon found to be activated directly by peroxyl radical systems without prior biotransformation to a diol derivative by the cytochrome P-450 system. These findings expand the range of potentially toxic substrates to be considered for activation by peroxyl radical pathways.