Liu Pei-Shan, Liu Ging-Hui, Chao Wei-Liang
Department of Microbiology, Soochow University, Shihlin, Taipei, Taiwan, ROC.
Toxicology. 2008 Feb 3;244(1):77-85. doi: 10.1016/j.tox.2007.11.005. Epub 2007 Nov 17.
Nonylphenol (NP) is the most critical metabolite of alkylphenol polyethoxylate detergents. NP is known as an endocrine disruptor with estrogenic activities and as an inhibitor of endoplasmic reticulum Ca(2+)-ATPase. Estrogen has modulatory roles on ligand-gated ion channels, such as nicotinic acetylcholine receptors (nAChRs). Ca(2+)-ATPase inhibitors can modulate the cytosolic calcium concentration (Ca(2+)]) and thus can affect the calcium signaling coupled with nAChRs. Therefore, NP is predicted to have complex effects on the Ca(2+) signaling and secretion coupled with nAChRs. This study investigated these effects using bovine adrenal chromaffin cells. The results show that NP suppressed the Ca(2+) signaling coupled with nAChRs and voltage-operated Ca(2+) channels in a dose-dependent manner, with IC(50)s of 1 and 5.9 microM, respectively. Estradiol exhibits similar suppression but much lower inhibitory potencies. NP alone induced a transient rise in Ca(2+) in the presence or absence of extracellular calcium. Thapsigargin, an endoplasmic reticulum Ca(2+)-ATPase inhibitor, partially suppressed the Ca(2+) rise induced by NP, but NP totally blocked the Ca(2+) rise induced by thapsigargin. This illustrates that NP can cause Ca(2+) release from thapsigargin-insensitive pools. Thapsigargin suppressed the Ca(2+) signaling coupled with nAChRs but increased that coupled with voltage-operated Ca(2+) channels. We propose that three routes are responsible for the effects of NP on nAChRs: named receptor channels, voltage-gated Ca(2+) channels, and Ca(2+)-induced Ca(2+) release. Three routes are related to the characteristics of NP as steroid-like compounds and Ca(2+)-ATPase inhibitor.
壬基酚（NP）是烷基酚聚乙氧基化物洗涤剂最关键的代谢产物。NP是一种具有雌激素活性的内分泌干扰物，也是内质网Ca(2+)-ATP酶的抑制剂。雌激素对配体门控离子通道具有调节作用，如烟碱型乙酰胆碱受体（nAChRs）。Ca(2+)-ATP酶抑制剂可调节胞质钙浓度（Ca(2+)），从而影响与nAChRs偶联的钙信号。因此，预计NP对与nAChRs偶联的Ca(2+)信号和分泌具有复杂影响。本研究使用牛肾上腺嗜铬细胞研究了这些影响。结果表明，NP以剂量依赖性方式抑制与nAChRs和电压门控Ca(2+)通道偶联的Ca(2+)信号，IC(50)分别为1和5.9 microM。雌二醇表现出类似的抑制作用，但抑制效力低得多。单独使用NP在有或没有细胞外钙的情况下均可诱导Ca(2+)短暂升高。毒胡萝卜素是一种内质网Ca(2+)-ATP酶抑制剂，可部分抑制NP诱导的Ca(2+)升高，但NP完全阻断了毒胡萝卜素诱导的Ca(2+)升高。这表明NP可导致从对毒胡萝卜素不敏感的钙库中释放Ca(2+)。毒胡萝卜素抑制与nAChRs偶联的Ca(2+)信号，但增加与电压门控Ca(2+)通道偶联的Ca(2+)信号。我们提出，NP对nAChRs的影响由三条途径介导：即受体通道、电压门控Ca(2+)通道和Ca(2+)诱导Ca(2+)释放。这三条途径与NP作为类固醇样化合物和Ca(2+)-ATP酶抑制剂的特性有关。
