Davila D R, Lane J L, Lauer F T, Burchiel S W
Toxicology Program, University of New Mexico College of Pharmacy, Albuquerque 87131, USA.
J Toxicol Environ Health A. 1999 Feb 26;56(4):249-61. doi: 10.1080/009841099158097.
It has been well established that certain polycyclic aromatic hydrocarbons (PAHs), such as 7,12-dimethylbenz[a]anthracene (DMBA), 3-methylcholanthrene (3MC), and benzo[a]pyrene (BaP), produce immunotoxicity and cancer in rodents and that these effects are also likely seen in humans. Our laboratory has found that polycyclic aromatic hydrocarbons (PAHs) produce an increase in intracellular Ca2+ in lymphocytes that appears to correlate with their immunotoxicity. Specifically, immunotoxic PAHs, such as DMBA and BaP, have been shown to produce a sustained increase in intracellular Ca2+ in lymphocytes, whereas nonimmunosuppressive PAHs, such as benzo[e]pyrene (BeP) and anthracene, do not. Our studies previously demonstrated that the rapid increase in intracellular Ca2+ produced by DMBA in HPB-ALL T cells was caused by protein tyrosine kinase (PTK) activation in human T cells, leading to tyrosine phosphorylation of phospholipase C (PLCgamma) and IP3-dependent Ca2+ mobilization. However, the specificity of PTK activation by PAHs was not established. In the present studies, we extend our observations of PTK activation by examining a number of PAHs for their effects on total and specific (Fyn and ZAP-70) PTK activity. We show that 10 microM concentrations of PAHs nonspecifically and rapidly (within 5 min) stimulate PTKs in the HPB-ALL human T cell line. BeP and anthracene were found to be nearly as effective at increasing total tyrosine kinase activity as DMBA, 3MC, and BaP, observed 5 min after exposure. We found that only immunotoxic PAHs activated the Fyn and ZAP-70 PTKs at 10 min, but total PTK activity was still increased by nonimmunotoxic PAHs, BeP, or anthracene after 10 min of exposure. These studies demonstrate that immunotoxic PAHs increase total and specific PTK activity in the human HPB-ALL T cell line. Thus the rapid increase in PTK activity produced by PAHs may not correlate with the immunotoxicity of these agents.
业已充分证实，某些多环芳烃（PAHs），如7,12 - 二甲基苯并[a]蒽（DMBA）、3 - 甲基胆蒽（3MC）和苯并[a]芘（BaP），可在啮齿动物中产生免疫毒性和致癌作用，并且这些影响在人类中也可能出现。我们实验室发现，多环芳烃（PAHs）可使淋巴细胞内的Ca2+增加，这似乎与其免疫毒性相关。具体而言，免疫毒性PAHs，如DMBA和BaP，已被证明可使淋巴细胞内的Ca2+持续增加，而非免疫抑制性PAHs，如苯并[e]芘（BeP）和蒽，则不会。我们之前的研究表明，DMBA在HPB - ALL T细胞中引起的细胞内Ca2+快速增加是由人T细胞中的蛋白酪氨酸激酶（PTK）激活所致，导致磷脂酶C（PLCγ）的酪氨酸磷酸化和IP3依赖性Ca2+动员。然而，PAHs对PTK激活的特异性尚未确定。在本研究中，我们通过检测多种PAHs对总PTK活性和特异性（Fyn和ZAP - 70）PTK活性的影响，扩展了对PTK激活的观察。我们发现，10 microM浓度的PAHs可在HPB - ALL人T细胞系中非特异性且快速（在5分钟内）刺激PTK。在暴露5分钟后观察到，BeP和蒽在增加总酪氨酸激酶活性方面几乎与DMBA、3MC和BaP一样有效。我们发现，仅免疫毒性PAHs在10分钟时激活Fyn和ZAP - 70 PTK，但在暴露10分钟后，非免疫毒性PAHs、BeP或蒽仍会使总PTK活性增加。这些研究表明，免疫毒性PAHs可增加人HPB - ALL T细胞系中的总PTK活性和特异性PTK活性。因此，PAHs引起的PTK活性快速增加可能与这些物质的免疫毒性无关。
