Krieger J A, Born J L, Burchiel S W
University of New Mexico College of Pharmacy, Toxicology Program, Albuquerque 87131.
Toxicol Appl Pharmacol. 1994 Aug;127(2):268-74. doi: 10.1006/taap.1994.1161.
The immunosuppressive synthetic methylated polycyclic aromatic hydrocarbon (PAH), 7,12-dimethylbenz[a]anthracene (DMBA), has been shown to cause both an immediate and a sustained elevation of free intracellular calcium (Ca2+) in human T cells. In the present studies, a series of anthracene- and pyrene-based PAHs were tested for rapid (3 min) and sustained (4 hr) Ca2+ mobilization in the HPB-ALL human T cell line measured by flow cytometry using Fluo-3 as a Ca2+ indicator. Immunosuppressive PAHs produced a sustained Ca2+ elevation for at least 4 hr, while weakly immunosuppressive PAHs caused only a transient increase in Ca2+. The immunosuppressive PAHs, DMBA, benzo[a]pyrene, dibenz[a,h]anthracene, and 9,10-dimethylanthracene, produced a sustained increase in intracellular Ca2+ in HPB-ALL cells. Those PAHs with moderate to minimal immunosuppressive properties (i.e., dibenz[a,c]anthracene, benz[a]anthracene, benzo[e]pyrene, and anthracene) produced small and transient Ca2+ mobilization responses in HPB-ALL cells. It appeared that methylation of anthracene at the 9,10-positions increased the duration of Ca2+ mobilization, whereas the addition of a benzene group in the "a" position was associated with a transient increase in Ca2+ levels. Genistein, a protein tyrosine kinase (PTK) inhibitor, partially inhibited the rapid and sustained PAH-induced Ca2+ mobilization responses, while the protein kinase C (PKC) inhibitors, staurosporine and calphostin C, had essentially no effect on PAH-induced Ca2+ elevation. It appears that the action of PAHs on PTKs is important in the rapid Ca2+ response of human T cells. However, additional biochemical mechanisms appear to be responsible for the sustained elevation of Ca2+ produced by PAHs in T cells. The results of these studies demonstrate that persistent elevation of intracellular Ca2+ by PAHs correlates with their known immunosuppressive properties.
免疫抑制性合成甲基化多环芳烃（PAH），7,12 - 二甲基苯并[a]蒽（DMBA），已被证明可导致人T细胞内游离钙（Ca2+）立即且持续升高。在本研究中，使用Fluo - 3作为Ca2+指示剂，通过流式细胞术检测了一系列基于蒽和芘的PAH在HPB - ALL人T细胞系中快速（3分钟）和持续（4小时）的Ca2+动员情况。免疫抑制性PAH可使Ca2+持续升高至少4小时，而弱免疫抑制性PAH仅引起Ca2+短暂升高。免疫抑制性PAH，如DMBA、苯并[a]芘、二苯并[a,h]蒽和9,10 - 二甲基蒽，可使HPB - ALL细胞内Ca2+持续升高。那些具有中度至最小免疫抑制特性的PAH（即二苯并[a,c]蒽、苯并[a]蒽、苯并[e]芘和蒽）在HPB - ALL细胞中产生小的且短暂的Ca2+动员反应。似乎蒽在9,10位的甲基化增加了Ca2+动员的持续时间，而在“a”位添加苯环与Ca2+水平短暂升高有关。金雀异黄素，一种蛋白酪氨酸激酶（PTK）抑制剂，部分抑制了PAH诱导的快速和持续的Ca2+动员反应，而蛋白激酶C（PKC）抑制剂，星形孢菌素和钙磷蛋白C，对PAH诱导的Ca2+升高基本没有影响。看来PAH对PTK的作用在人T细胞的快速Ca2+反应中很重要。然而，其他生化机制似乎负责PAH在T细胞中产生的Ca2+持续升高。这些研究结果表明，PAH引起的细胞内Ca2+持续升高与其已知的免疫抑制特性相关。
