Inhibition of rat brain phosphatidylinositol-specific phospholipase C by aluminum: regional differences, interactions with aluminum salts, and mechanisms.
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.
Nostrandt
A C
AC
Curriculum in Toxicology, University of North Carolina at Chapel Hill 27599, USA.
Shafer
T J
TJ
Mundy
W R
WR
Padilla
S
S
D000077410:Aluminum Chloride; D017607:Aluminum Compounds / Q000633:toxicity*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002531:Cerebellum / Q000187:drug effects / Q000201:enzymology; D002712:Chlorides / Q000633:toxicity*; D003342:Corpus Striatum / Q000187:drug effects / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D005625:Frontal Lobe / Q000187:drug effects / Q000201:enzymology; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology; D006868:Hydrolysis; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008297:Male; D043265:Phosphatidylinositol Diacylglycerol-Lyase; D010726:Phosphodiesterase Inhibitors / Q000633:toxicity*; D054801:Phosphoinositide Phospholipase C; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D051381:Rats; D014018:Tissue Distribution
D017607:Aluminum Compounds; D002712:Chlorides; D010726:Phosphodiesterase Inhibitors; D000077410:Aluminum Chloride; D010727:Phosphoric Diester Hydrolases; D054801:Phosphoinositide Phospholipase C; D043265:Phosphatidylinositol Diacylglycerol-Lyase; D002118:Calcium