Inhibition of sarcoplasmic/endoplasmic reticulum calcium ATPases (SERCA) by polycyclic aromatic hydrocarbons in HPB-ALL human T cells and other tissues.
Inhibition of sarcoplasmic/endoplasmic reticulum calcium ATPases (SERCA) by polycyclic aromatic hydrocarbons in HPB-ALL human T cells and other tissues.
复制标题
HPB-ALL 人 T 细胞和其他组织中多环芳烃对肌浆/内质网钙 ATP 酶 (SERCA) 的抑制。
DOI：
10.1006/taap.1995.1131
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发表时间：
1995
期刊：
影响因子：
--
通讯作者：
Burchiel,SW
中科院分区：
文献类型：
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作者：
Krieger,JA;Davila,DR;Lytton,J;Born,JL;Burchiel,SW
多环芳烃(PAHs)是环境中发现的一种免疫抑制化学物质，已被证明可以破坏人和小鼠淋巴细胞内钙稳态和钙依赖信号。许多多环芳烃能使淋巴细胞内游离钙离子迅速持续增加。钙离子持续扰动的机制尚不清楚。在本研究中，免疫毒性多环芳烃7，12-二甲基苯并[a]蒽、苯并[a]芘、苯并[a]蒽和9，10-二甲基蒽的浓度分别为0.1、1和10μM时，可显著抑制由15,000g人T细胞裂解物上清液制备的囊泡对ATP依赖性的45Ca~(2+)吸收，但免疫毒性较小的化合物菲(ANT)和苯并[e]芘(BEP)对其无明显抑制作用。以已知的ATPase抑制剂为对照，通过定量测定在存在或不存在多环芳烃的情况下ATP的水解酶活性来确定其催化活性。在10μM时，DMBA和BAP显著减少了无机磷的形成(约为对照的65%)，而蚂蚁和BEP仅引起了轻微的活性降低(10μM时为对照的10%)。菲可部分逆转DMBA和BAP对ATP水解酶的抑制作用。DMBA和BAP均抑制所有已知的SERCA型Ca~(2+)-ATPase的活性，而ANT和BEP则不抑制，但对Na~+，K~+-ATPase和质膜Ca~(2+)-ATPase活性均无影响。这些结果表明，免疫毒性和致癌的多环芳烃在不同物种的人淋巴细胞和含SERCA的组织中具有thapsigargin样效应。SERCA活性的抑制可能在改变淋巴细胞和其他组织的钙稳态中起重要作用。
Polycyclic aromatic hydrocarbons (PAHs) are immunosuppressive chemicals found in the environment that have been shown to disrupt intracellular Ca2+homeostasis and Ca2+-dependent signaling in human and murine lymphocytes. Many PAHs produce a rapid and sustained increase in intracellular free Ca2+in lymphocytes. The mechanism of persistent Ca2+perturbation remains undefined. In the present studies, ATP-dependent45Ca2+uptake into vesicles prepared from a 15,000g supernatant of HPB-ALL human T cell lysates was significantly inhibited by 0.1, 1, and 10 μM concentrations of the immunotoxic PAHs 7, 12-dimethylbenz[a]anthracene (DMBA), benzo[a]pyrene (BAP), benz[a]anthracene, and 9,10-dimethylanthracene, but not by the less immunotoxic compounds anthracene (ANT) and benzo[e]pyrene (BEP). Ca2+-ATPase catalytic activity was determined by quantitating hydrolysis of ATP in the presence or absence of PAHs, with known ATPase inhibitors included as controls. Formation of inorganic phosphate was significantly decreased (>65% of control at 10 μM) by DMBA and BAP, whereas ANT and BEP caused only a slight reduction in activity (10% of control at 10 μM). Anthracene partially reversed the inhibitory effect of DMBA and BAP on ATP hydrolysis when agents were coincubated. Both DMBA and BAP, but not ANT and BEP, inhibited the activity of all known SERCA-type Ca2+-ATPases, while not affecting either Na+, K+-ATPase activity or plasma membrane Ca2+-ATPase activities. These results demonstrate that immunotoxic and carcinogenic polycyclic aromatic hydrocarbons have a thapsigargin-like effect in human lymphocytes and SERCA-containing tissues from various species. Inhibition of SERCA activity may play an important role in altered Ca2+homeostasis in lymphocytes and other tissues.