Nostrandt A C, Shafer T J, Mundy W R, Padilla S
Curriculum in Toxicology, University of North Carolina at Chapel Hill 27599, USA.
Toxicol Appl Pharmacol. 1996 Jan;136(1):118-25. doi: 10.1006/taap.1996.0014.
We have shown previously that aluminum chloride (AlCl3, 10-500 microM) inhibits hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) by phosphatidylinositol-specific phospholipase C (PI-PLC) in a concentration-dependent manner. In the present study, we characterize further the effects of aluminum on PI-PLC. A comparison of different brain regions and liver revealed varying basal PI-PLC specific activities, as well as differential susceptibility to inhibition by 100 microM AlCl3. The hippocampus had the highest specific activity of PI-PLC, followed by striatum, frontal cortex, cerebellum, and liver. PI-PLC inhibition by 100 microM AlCl3 was greatest in the liver, followed by cerebellum, hippocampus, cortex, and striatum. Moreover, 100 microM AlCl3 or aluminum lactate (Al (lac)) were similarly effective at inhibiting PI-PLC activity in rat cortical tissue. Addition of AlCl3 (100 microM) decreased PI-PLC activity at CaCl2 concentrations ranging from 0 to 2 mM; however, AlCl3 did not affect the shape of the calcium concentration curve, suggesting that aluminum does not inhibit PI-PLC activity by interference with the cofactor, calcium. AlCl3 (100 microM) did inhibit rat cortical PI-PLC hydrolysis of PIP2 in a competitive manner. These results demonstrate some regional/tissue differences in PI-PLC activity and its sensitivity to aluminum, and effects of AlCl3 and Al(lac) consistent with the effects previously noted in PI turnover in brain slices. Furthermore, our results suggest that competitive inhibition of PLC-mediated PIP2 hydrolysis by aluminum is a potential mechanism by which aluminum may cause the disruptions phosphoinositide signaling which have been reported following in vivo and in vitro exposure.
我们之前已经表明，氯化铝（AlCl3，10 - 500微摩尔）以浓度依赖的方式抑制磷脂酰肌醇特异性磷脂酶C（PI - PLC）对磷脂酰肌醇4,5 - 二磷酸（PIP2）的水解。在本研究中，我们进一步表征了铝对PI - PLC的影响。对不同脑区和肝脏的比较显示，基础PI - PLC比活性不同，以及对100微摩尔AlCl3抑制的敏感性差异。海马体的PI - PLC比活性最高，其次是纹状体、额叶皮质、小脑和肝脏。100微摩尔AlCl3对PI - PLC的抑制在肝脏中最大，其次是小脑、海马体、皮质和纹状体。此外，100微摩尔AlCl3或乳酸铝（Al（lac））在抑制大鼠皮质组织中的PI - PLC活性方面同样有效。添加AlCl3（100微摩尔）在CaCl2浓度范围从0到2毫摩尔时降低了PI - PLC活性；然而，AlCl3不影响钙浓度曲线的形状，表明铝不是通过干扰辅因子钙来抑制PI - PLC活性。AlCl3（100微摩尔）确实以竞争性方式抑制大鼠皮质PI - PLC对PIP2的水解。这些结果证明了PI - PLC活性及其对铝的敏感性存在一些区域/组织差异，以及AlCl3和Al（lac）的作用与先前在脑片PI周转中所观察到的作用一致。此外，我们的结果表明，铝对PLC介导的PIP2水解的竞争性抑制是铝可能导致体内和体外暴露后所报道的磷酸肌醇信号传导破坏的一种潜在机制。
