选定的间位和对位羟基化的非二噁英类多氯联苯的构效关系：从单个 RyR1 通道到肌肉功能障碍。
Structure-activity relationship of selected meta- and para-hydroxylated non-dioxin like polychlorinated biphenyls: from single RyR1 channels to muscle dysfunction.
机构信息
* Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, California 95616;
出版信息
Toxicol Sci. 2013 Dec;136(2):500-13. doi: 10.1093/toxsci/kft202. Epub 2013 Sep 7.
Non-dioxin like polychlorinated biphenyls (NDL-PCBs) are legacy environmental contaminants with contemporary unintentional sources. NDL-PCBs interact with ryanodine receptors (RyRs), Ca(2+) channels of sarcoplasmic/endoplasmic reticulum (SR/ER) that regulate excitation-contraction coupling (ECC) and Ca(2+)-dependent cell signaling in muscle. Activities of 4 chiral congeners PCB91, 95, 132, and 149 and their respective 4- and 5-hydroxy (-OH) derivatives toward rabbit skeletal muscle ryanodine receptor (RyR1) are investigated using [(3)H]ryanodine binding and SR Ca(2+) flux analyses. Although 5-OH metabolites have comparable activity to their respective parent in both assays, 4-OH derivatives are unable to trigger Ca(2+) release from SR microsomes in the presence of Ca(2+)-ATPase activity. PCB95 and derivatives are investigated using single channel voltage-clamp and primary murine embryonic muscle cells (myotubes). Like PCB95, 5-OH-PCB95 quickly and persistently increases channel open probability (p o > .9) by stabilizing the full-open channel state, whereas 4-OH-PCB95 transiently enhances p o. Ca(2+) imaging of myotubes loaded with Fluo-4 show that acute exposure to PCB95 (5 µM) potentiates ECC and caffeine responses and partially depletes SR Ca(2+) stores. Exposure to 5-OH-PCB95 (5 µM) increases cytoplasmic Ca(2+), leading to rapid ECC failure in 50% of myotubes with the remainder retaining negligible responses. 4-OH-PCB95 neither increases baseline Ca(2+) nor causes ECC failure but depresses ECC and caffeine responses by 50%. With longer (3h) exposure to 300 nM PCB95, 5-OH-PCB95, or 4-OH-PCB95 decreases the number of ECC responsive myotubes by 22%, 81%, and 51% compared with control by depleting SR Ca(2+) and/or uncoupling ECC. NDL-PCBs and their 5-OH and 4-OH metabolites differentially influence RyR1 channel activity and ECC in embryonic skeletal muscle.
非二恶英类多氯联苯（NDL-PCBs）是具有当代非故意来源的遗留环境污染物。NDL-PCBs 与肌浆网/内质网（SR/ER）的肌质网钙通道（RyR）相互作用，调节兴奋-收缩偶联（ECC）和肌肉中依赖 Ca(2+)的细胞信号转导。使用 [(3)H]ryanodine 结合和 SR Ca(2+)通量分析研究了 4 种手性同系物 PCB91、95、132 和 149 及其各自的 4-和 5-羟基（-OH）衍生物对兔骨骼肌肌质网钙通道（RyR1）的活性。尽管 5-OH 代谢物在两种测定中与各自的母体具有相当的活性，但 4-OH 衍生物在 Ca(2+)-ATPase 活性存在下无法从 SR 微粒体引发 Ca(2+)释放。使用单通道电压钳和原代鼠胚胎肌肉细胞（肌管）研究 PCB95 和衍生物。与 PCB95 一样，5-OH-PCB95 通过稳定全开放通道状态，快速且持续地增加通道开放概率（p o >.9），而 4-OH-PCB95 则短暂增强 p o 。用 Fluo-4 负载的肌管进行 Ca(2+)成像显示，急性暴露于 PCB95（5 µM）增强 ECC 和咖啡因反应，并部分耗尽 SR Ca(2+)储存。暴露于 5-OH-PCB95（5 µM）会增加细胞质 Ca(2+)，导致 50%的肌管迅速发生 ECC 失败，其余肌管保持可忽略不计的反应。4-OH-PCB95 既不增加基础 Ca(2+)，也不会导致 ECC 失败，但会使 ECC 和咖啡因反应降低 50%。与对照相比，用 300 nM PCB95、5-OH-PCB95 或 4-OH-PCB95 进行 3 小时的长期暴露，分别使 22%、81%和 51%的 ECC 反应性肌管数量减少，这是通过耗尽 SR Ca(2+)和/或使 ECC 解偶联所致。NDL-PCBs 及其 5-OH 和 4-OH 代谢物可影响胚胎骨骼肌中的 RyR1 通道活性和 ECC。
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