EFFECTS OF ALUMINUM ON THE HEPATIC INOSITOL POLYPHOSPHATE PHOSPHATASE

There is speculation that some of the toxic effects of Al3+ may origin ate from it perturbing inositol phosphate/Ca2+ signalling. For example , in permeabilized L1210 mouse lymphoma cells, 10-50 mu M Al3+ activat ed Ins(1,3,4,5)P-4-dependent Ca2+ mobilization and Ins(1,3,4,5)P-4 3-p hosphatase activity [Loomis-Husselbee, Cullen,Irvine and Dawson (1991) Biochem. J. 277, 883-885]. Ins(1,3,4,5)P-4 3-phosphatase activity is performed by a multiple inositol polyphosphate phosphatase (MIPP) that also attacks Ins(1,3,4,5,6)P-5 and InsP(6), [Craxton, Ali and Shears (1995) Biochem. J. 305, 491-498] : 5-50 mu M Al3+ increased MIPP activ ity towards both Ins(1,3,4,5)P-4 (by 30%) and Ins(1,3,4,5,6)P-5 (by up to 500 %), without affecting metabolism of InsP(6). Higher concentrat ions of Al3+ inhibited metabolism of all three substrates, and in the case of InsP(6), Al3+ altered the pattern of accumulating products. Wh en 1-50 mu M Al3+ was present, InsP(6) became a less effective inhibit or of Ins(1,3,4,5)P-4 3-phosphatase activity; this effect did not depe nd on the presence of cellular membranes, contrary to a previous propo sal. The latter phenomenon largely explains how, in a cell-free system where Ins(1,3,4,5)P-4 3-phosphatase is inhibited by endogenous InsP(6 ), the addition of Al3+ can apparently increase the enzyme activity. H owever, there was no effect of either 10 or 25 mu M Al3+ (in either th e presence or absence of apotransferrin) on inositol phosphate profile s in either Jurkat E6-1 lymphoma cells or AR4-2J pancreatoma cells.