Metabolic activation of PCBs to quinones: Reactivity toward nitrogen and sulfur nucleophiles and influence of superoxide dismutase
Metabolic activation of PCBs to quinones: Reactivity toward nitrogen and sulfur nucleophiles and influence of superoxide dismutase
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DOI：
10.1021/tx950117e
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发表时间：
1996-04-01
影响因子：
4.1
通讯作者：
Robertson, LW
中科院分区：
文献类型：
--
作者：
Amaro, AR;Oakley, GG;Robertson, LW
多氯联苯（PCBs）可能经过细胞色素p -450催化的羟基化反应形成氯化的二羟基联苯代谢物。当羟基互为邻位或对位时，细胞内的过氧化物酶可催化氧化生成醌。为了研究多氯联苯衍生醌类化合物的反应性，合成了部分氯苯基1,2-和1,4-苯醌类化合物，并对其在饱和甘汞电极上的还原电位进行了表征。用2,3-二氯-5,6-二氰-1,4-苯醌氧化相应的二羟基联苯，得到了4-（4'-氯苯基）-1,2-和4-（3',4'-二氯苯基）-1,2-苯醌。通过Meerwein芳化反应合成了6种1,4-苯醌：2-（2′-氯苯基）-1,4-,2-（3′-氯苯基）1,4-,2-（4′-氯苯基）-1,4-,2-（2′，5′-二氯苯基）-1,4-,2-（3′，4′-二氯苯基）-1,4-和2-（3′，4′-二氯苯基）-1,4-和2-（3′，5′-二氯苯基）-1,4-和2-（3′，5′-二氯苯基）-1,4-。作为模型研究，在pH 7.4的准一级条件下，测定了2-（4′-氯苯基）-1,4-苯醌对氮亲核试剂甘氨酸、l -精氨酸、l -组氨酸和l -赖氨酸的反应速率。速率常数范围为0.45 ~ 0.75 min(-1) M（-1）。ph越高，反应速率越高。两种反应产物以1:4的比例被鉴定为5环和6环加成产物。相反，2-（4′-氯苯基）-1,4-苯醌与硫亲核试剂谷胱甘肽或n -乙酰- l-半胱氨酸的反应是瞬间的。谷胱甘肽与2-（4′-氯苯基）-1,4-苯醌反应的主要产物也是g环加成产物。对苯二酚硫醚可以酶促再氧化为醌硫醚。此外，还研究了大气氧和超氧化物歧化酶对辣根过氧化物酶/ h2o2催化氧化3,4-二氯-2′，5′-二羟基联苯制2-（3′，4′-二氯苯）-1,4-苯醌和3,4-二氯- 3′，4′-二氯苯制4-（3′，4′-二氯苯）-1,2-苯醌速率的影响。虽然大气中氧气的存在或不存在不会改变氧化反应的速率，但超氧化物歧化酶的存在显著增加了两种氧化反应的速率，对1,4-对苯二酚的氧化有更大的影响。这些数据表明，多氯联苯衍生的醌与细胞中的氮和硫亲核试剂反应，这可能部分解释了个别多氯联苯和多氯联苯配方的毒性作用，如谷胱甘肽耗竭，氧化应激和细胞死亡
Polychlorinated biphenyls (PCBs) may undergo cytochrome P-450-catalyzed hydroxylations to form chlorinated dihydroxybiphenyl metabolites. When the hydroxyl groups are ortho or para to each other, oxidation to a quinone may be catalyzed by peroxidases present within the cell. In order to study the reactivity of PCB-derived quinones, selected chlorophenyl 1,2- and 1,4-benzoquinones were synthesized and characterized, including their reduction potentials against a saturated calomel electrode. Two quinones, 4-(4'-chlorophenyl)-1,2-, and 4-(3',4'-dichlorophenyl)-1,2-benzoquinone, were obtained via the oxidation of the corresponding dihydroxybiphenyls with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone. Six 1,4-benzoquinones were synthesized via the Meerwein arylation: 2-(2'-chlorophenyl)-1,4-, 2-(3'-chlorophenyl)1,4-, 2-(4'-chlorophenyl)-1,4-, 2-(2',5'-dichlorophenyl)-1,4-, 2-(3',4'-dichlorophenyl)-1,4-, and 2-(3',5'-dichlorophenyl)-1,4-benzoquinone. As a model study, the rate of reactivity of 2-(4'-chlorophenyl)-1,4-benzoquinone toward the nitrogen nucleophiles glycine, L-arginine, L-histidine- and L-lysine was determined under pseudo-first-order conditions at pH 7.4. The rate constants ranged from 0.45 to 0.75 min(-1) M(-1). Higher rates were obtained under conditions of higher pH. Two reaction products were identified as the 5- and 6-ring addition products in the ratio of 1:4. In contrast, the reaction of 2-(4'-chlorophenyl)-1,4-benzoquinone with the sulfur nucleophiles glutathione or N-acetyl-L-cysteine was instantaneous. The major product of the reaction of glutathione with 2-(4'-chlorophenyl)-1,4-benzoquinone was also the g-ring addition product. The hydroquinone thioether could be enzymatically reoxidized to the quinone thioether. Also, the influence of atmospheric oxygen and superoxide dismutase on the rates of the following horseradish peroxidase/H2O2-catalyzed oxidations was investigated: 3,4-dichloro-2',5'-dihydroxybiphenyl to 2-(3',4'-dichlorophenyl)-1,4-benzoquinone and 3,4-dichloro- 3',4'-dihydroxybiphenyl to 4-(3',4'-dichlorophenyl)-1,2-benzoquinone. While the presence or absence of atmospheric oxygen did not alter the rates of the oxidation reactions, the presence of superoxide dismutase significantly increased the rates of both oxidation reactions, having the greater effect on the oxidation of the 1,4-hydroquinone, These data show that PCB-derived quinones react with both nitrogen and sulfur nucleophiles of the cell and may explain, in part, the toxic effects of individual PCBs and PCB formulations, such as glutathione depletion, oxidative stress, and cell death.