Atropselective Oxidation of 2,2′,3,3′,4,6′-Hexachlorobiphenyl (PCB 132) to Hydroxylated Metabolites by Human Liver Microsomes and Its Implications for PCB 132 Neurotoxicity
Atropselective Oxidation of 2,2′,3,3′,4,6′-Hexachlorobiphenyl (PCB 132) to Hydroxylated Metabolites by Human Liver Microsomes and Its Implications for PCB 132 Neurotoxicity
复制标题
人肝微粒体将 2,2-,3,3-,4,6-六氯联苯 (PCB 132) 选择性氧化成羟基代谢物及其对 PCB 132 神经毒性的影响
DOI：
10.1093/toxsci/kfz150
复制
发表时间：
2019
影响因子：
3.8
通讯作者：
Lehmler, Hans-Joachim
中科院分区：
文献类型：
--
作者：
Uwimana, Eric;Cagle, Brianna;Yeung, Coby;Li, Xueshu;Patterson, Eric V.;Doorn, Jonathan A.;Lehmler, Hans-Joachim
多氯联苯（PCBs）与神经发育障碍有关。几种神经毒性同系物显示轴向手性和atropselectively影响涉及多氯联苯神经毒性的细胞目标。关于这些同源物在人体内的选择性代谢及其对神经毒性结果的选择性影响，现有资料有限。本文研究了人肝微粒体（HLM）对2，2 ′，3，3 ′，4，6 ′-六氯联苯（PCB 132）的氧化作用及其对培养的多巴胺能细胞的作用是选择性的假说。将外消旋PCB 132与合并或单一供体HLM孵育，并通过气相色谱法测定PCB 132及其代谢物的水平和对映体分数。主要代谢产物为2，2 ′，3，4，4 ′，6 ′-六氯联苯-3 ′-醇（3′-140）或2，2 ′，3，3 ′，4，6 ′-六氯联苯-5 ′-醇（5′-132）。PCB 132代谢物谱显示个体间差异，并取决于PCB 132阻转异构体。计算研究表明，3′-140是通过3，4-芳烃氧化物中间体形成的。PCB 132的第二洗脱阻转异构体、3′-140的第一洗脱阻转异构体和5′-132的第二洗脱阻转异构体在所有HLM孵育物中富集。PCB 132代谢物的对映体组分在研究的单一供体HLM制剂之间仅略有不同。多巴胺能细胞暴露于纯PCB 132阻转异构体24小时后，活性氧和多巴胺及其代谢产物的水平没有显着改变。这些研究结果表明，在人体中，PCB 132向其代谢物的阻转选择性生物转化存在个体差异;然而，由此产生的PCB 132阻转异构体富集不太可能影响与研究中研究的终点相关的神经毒性结果。
Polychlorinated biphenyls (PCBs) have been associated with neurodevelopmental disorders. Several neurotoxic congeners display axial chirality and atropselectively affect cellular targets implicated in PCB neurotoxicity. Only limited information is available regarding the atropselective metabolism of these congeners in humans and their atropselective effects on neurotoxic outcomes. Here we investigate the hypothesis that the oxidation of 2,2′,3,3′,4,6′-hexachlorobiphenyl (PCB 132) by human liver microsomes (HLMs) and their effects on dopaminergic cells in culture are atropselective. Racemic PCB 132 was incubated with pooled or single donor HLMs, and levels and enantiomeric fractions of PCB 132 and its metabolites were determined gas chromatographically. The major metabolite was either 2,2′,3,4,4′,6′-hexachlorobiphenyl-3′-ol (3′-140), a 1,2-shift product, or 2,2′,3,3′,4,6′-hexachlorobiphenyl-5′-ol (5′-132). The PCB 132 metabolite profiles displayed interindividual differences and depended on the PCB 132 atropisomer. Computational studies suggested that 3′-140 is formed via a 3,4-arene oxide intermediate. The second eluting atropisomer of PCB 132, first eluting atropisomer of 3′-140, and second eluting atropisomer of 5′-132 were enriched in all HLM incubations. Enantiomeric fractions of the PCB 132 metabolites differed only slightly between the single donor HLM preparations investigated. Reactive oxygen species and levels of dopamine and its metabolites were not significantly altered after a 24 h exposure of dopaminergic cells to pure PCB 132 atropisomers. These findings suggest that there are interindividual differences in the atropselective biotransformation of PCB 132 to its metabolites in humans; however, the resulting atropisomeric enrichment of PCB 132 is unlikely to affect neurotoxic outcomes associated with the endpoints investigated in the study.