Effects of aluminium on the hepatic inositol polyphosphate phosphatase.
There is speculation that some of the toxic effects of Al3+ may originate from it perturbing inositol phosphate/Ca2+ signalling. For example, in permeabilized L1210 mouse lymphoma cells, 10-50 microM Al3+ activated Ins(1,3,4,5)P4-dependent Ca2+ mobilization and Ins(1,3,4,5)P4 3-phosphatase activity [Loomis-Husselbee, Cullen, Irvine and Dawson (1991) Biochem. J. 277, 883-885]. Ins(1,3,4,5)P4 3-phosphatase activity is performed by a multiple inositol polyphosphate phosphatase (MIPP) that also attacks Ins(1,3,4,5,6)P5 and InsP6 [Craxton, Ali and Shears (1995) Biochem. J. 305, 491-498]: 5-50 microM Al3+ increased MIPP activity towards both Ins(1,3,4,5)P4 (by 30%) and Ins(1,3,4,5,6)P5 (by up to 500%), without affecting metabolism of InsP6. Higher concentrations of Al3+ inhibited metabolism of all three substrates, and in the case of InsP6, Al3+ altered the pattern of accumulating products. When 1-50 microM Al3+ was present, InsP6 became a less effective inhibitor of Ins(1,3,4,5)P4 3-phosphatase activity; this effect did not depend on the presence of cellular membranes, contrary to a previous proposal. The latter phenomenon largely explains how, in a cell-free system where Ins(1,3,4,5)P4 3-phosphatase is inhibited by endogenous InsP6, the addition of Al3+ can apparently increase the enzyme activity. However, there was no effect of either 10 or 25 microM Al3+ (in either the presence or absence of apotransferrin) on inositol phosphate profiles in either Jurkat E6-1 lymphoma cells or AR4-2J pancreatoma cells.
Inositol Lipid Section, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709.
N
N
Ali
A
A
Craxton
M
M
Sumner
S B
SB
Shears
D000535:Aluminum / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism*; D008862:Microsomes, Liver / Q000201:enzymology*; D010744:Phosphoric Monoester Hydrolases / Q000187:drug effects*; D010833:Phytic Acid / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D007295:Inositol Phosphates; D010833:Phytic Acid; D000535:Aluminum; D010744:Phosphoric Monoester Hydrolases; C064119:multiple inositol-polyphosphate phosphatase; C061816:phosphatidylinositol-3-phosphatase