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PubMed1986

Isolation and characterization of the inositol cyclic phosphate products of phosphoinositide cleavage by phospholipase C. Metabolism in cell-free extracts.

The phosphoinositides are metabolized by phospholipase C in response to hormone or agonist stimulation in many cell types to produce diglyceride and water-soluble inositol phosphates. We have recently shown that the phospholipase C reaction products include cyclic phosphate esters of inositol. One of these, inositol 1, 2-cyclic 4,5-trisphosphate, is active in promoting Ca2+ mobilization in platelets and in inducing changes in conductance in Limulus photoreceptors similar to those produced by light (Wilson, D. B., Connolly, T. M., Bross, T. E., Majerus, P. W., Sherman, W. R., Tyler, A., Rubin, L. J., and Brown, J. E. (1985) J. Biol. Chem. 260, 13496-13501. In the current study, we have examined the metabolism of the inositol phosphates. We find that both cyclic and non-cyclic inositol trisphosphates are metabolized by inositol 1,4,5-trisphosphate 5-phosphomonoesterase, to inositol 1,2-cyclic bisphosphate and inositol 1,4-bisphosphate, respectively. However, the apparent Km of the enzyme for the cyclic substrate is approximately 10-fold higher than for the non-cyclic substrate. These inositol bisphosphates are more slowly degraded to inositol 1,2-cyclic phosphate and inositol 1-phosphate, respectively. Inositol 1,2-cyclic phosphate is then hydrolyzed to inositol 1-phosphate, which in turn is degraded to inositol and inorganic phosphate by inositol 1-phosphate phosphatase. The human platelet inositol 1,2-cyclic phosphate hydrolase enzyme and a similar rat kidney hydrolase do not utilize the cyclic polyphosphate esters of inositol as substrates. These results suggest that the inositol cyclic phosphates and the non-cyclic inositol phosphates are metabolized separately by phosphatases to cyclic and non-cyclic inositol monophosphates. The cyclic monophosphate is then converted to inositol 1-phosphate by a cyclic hydrolase. We suggest that the enzymes that metabolize the inositol phosphates may serve to regulate cellular responses to these compounds.

Animals↗
PubMed1987

Metabolism of inositol 1,4,5-trisphosphate in guinea-pig hepatocytes.

Metabolism of inositol 1,4,5-trisphosphate was investigated in permeabilized guinea-pig hepatocytes. The conversion of [3H]inositol 1,4,5-trisphosphate to a more polar 3H-labelled compound occurred rapidly and was detected as early as 5 s. This material co-eluted from h.p.l.c. with inositol 1,3,4,5 tetrakis[32P]phosphate and is presumably an inositol tetrakisphosphate. A significant increase in the 3H-labelled material co-eluting from h.p.l.c. with inositol 1,3,4-trisphosphate occurred only after a definite lag period. Incubation of permeabilized hepatocytes with inositol 1,3,4,5-tetrakis[32P]phosphate resulted in the formation of 32P-labelled material that co-eluted with inositol 1,3,4-trisphosphate; no inositol 1,4,5-tris[32P]phosphate was produced, suggesting the action of a 5-phosphomonoesterase. The half-time of hydrolysis of inositol 1,3,4,5-tetrakis[32P]phosphate of approx. 1 min was increased to 3 min by 2,3-bisphosphoglyceric acid. Similarly, the rate of production of material tentatively designed as inositol 1,3,4-tris[32P]phosphate from the tetrakisphosphate was reduced by 10 mM-2,3-bisphosphoglyceric acid. In the absence of ATP there was no conversion of [3H]inositol 1,4,5-trisphosphate to [3H]inositol tetrakisphosphate or to [3H]inositol 1,3,4-trisphosphate, which suggests that the 1,3,4 isomer does not result from isomerization of inositol 1,4,5-trisphosphate. The results of this study suggest that the origin of the 1,3,4 isomer of inositol trisphosphate in isolated hepatocytes is inositol 1,3,4,5-tetrakisphosphate and that inositol 1,4,5-trisphosphate is rapidly converted to this tetrakisphosphate. The ability of 2,3-bisphosphoglyceric acid, an inhibitor of 5-phosphomonoesterase of red blood cell membrane, to inhibit the breakdown of the tetrakisphosphate suggests that the enzyme which removes the 5-phosphate from inositol 1,4,5-trisphosphate may also act to convert the tetrakisphosphate to inositol 1,3,4-trisphosphate. It is not known if the role of inositol 1,4,5-trisphosphate kinase is to inactivate inositol 1,4,5-trisphosphate or whether the tetrakisphosphate product may have a messenger function in the cell.

2,3-Diphosphoglycerate↗
PubMed1991

Acute and chronic exposure of mouse cerebral microvessel endothelial cells to increased concentrations of glucose and galactose: effect on myo-inositol metabolism, PGE2 synthesis, and Na+/K(+)-ATPase transport activity.

Cultured mouse cerebral microvessel endothelial cells have a large intracellular myo-inositol content and rapidly take up extracellular myo-inositol. Myo-inositol uptake occurs by a high- and low-affinity transport system. Both transport systems appear to be Na(+)-dependent. The high- and low-affinity transport systems have a Km of 11 and 198 mumol/L and a Vmax of 47 and 381 pmol/min/mg protein, respectively. Acute exposure of cultured cells to 30 mmol/L D-glucose or D-galactose causes a decrease in myo-inositol uptake. The acute effect of glucose and galactose on myo-inositol uptake is sensitive to the extracellular myo-inositol concentration. The acute effect of glucose is apparently due to a competitive inhibition of high-affinity myo-inositol transport and has a Ki of 21 mmol/L. L-Glucose is more effective than D-glucose in decreasing myo-inositol uptake. In contrast, 2-deoxyglucose or 3-0-methylglucose does not acutely inhibit myo-inositol uptake. This suggests that the hydroxyl groups on carbons 2 and 3 of glucose are necessary for inhibitory activity. Chronic exposure of cells to media containing 136.4 mumol/L myo-inositol and 30 mmol/L glucose has no effect on myo-inositol accumulation from the extracellular fluid, myo-inositol incorporation into inositol phospholipids, or total myo-inositol content. Chronic exposure of the cells to media containing 30 mmol/L glucose causes only a small increase in the intracellular sorbitol content. In contrast, chronic exposure of the cells to media containing 30 mmol/L galactose causes a large increase in galactitol content and a decrease in myo-inositol accumulation, myo-inositol incorporation into inositol phospholipids, and intracellular myo-inositol content. Sorbinil treatment of the galactose-supplemented media protects the cells form changes in myo-inositol metabolism and content. Chronic exposure of the cells to media containing 30 mmol/L glucose or 30 mmol/L galactose causes a decrease in ouabain-sensitive Na+/K(+)-ATPase transport activity, which is corrected by the addition of sorbinil to the media. Chronic exposure of the cells to media containing 45 mmol/L glucose, but not galactose, causes an increase in PGE2 production. These studies suggest that acute or chronic exposure of cultured microvessel endothelial cells to increased concentrations of glucose or galactose causes a decrease in myo-inositol uptake by different mechanisms. Chronic exposure of the cells to increased concentrations of glucose or galactose causes alterations in endothelial cell properties, including Na+/K(+)-ATPase transport activity and eicosanoid synthesis. The data are not clearly supportive of polyol accumulation and myo-inositol depletion as being responsible for the decrease in Na+/K+ pump activity.

Animals↗
PubMed1993

The uptake of 3H-labelled monodeoxyfluoro-myo-inositols into thymocytes and their incorporation into phospholipid in permeabilized cells.

Monodeoxyfluoro-myo-inositols were applied to electropermeabilized and intact thymocyte preparations to study their metabolism and uptake in order to investigate their suitability as potential inhibitors of phosphoinositide-mediated cellular responses. Only three of the monodeoxyfluoro-myo-inositols were incorporated into the phospholipids of thymocytes: 1D-3-deoxy-3-fluoro-myo-inositol, 5-deoxy-5-fluoro-myo-inositol and 1D-6-deoxy-6-fluoro-myo-inositol, all of which were weaker substrates for phosphatidylinositol synthase than was myo-inositol. The 3-, 5- and 6-fluoro analogues also behaved as competitive inhibitors, with K1 values of 350 +/- 5 microM, 350 +/- 5 microM and 2.9 +/- 2 mM respectively, compared with a Km for myo-inositol of 31 +/- 4 microM. When incubated with electropermeabilized thymocyte preparations, these three analogues of myo-inositol all formed phospholipids with chromatographic properties which corresponded to those of substituted phosphatidylinositol and phosphatidylinositol monophosphate. The uptake of myo-inositol and of the monodeoxyfluoro-myo-inositols into intact thymocytes was studied by a dual-label technique. All the monodeoxyfluoro-myo-inositols were taken up to some extent, but only 2-deoxy-2-fluoro-myo-inositol and 1D-3-deoxy-3-fluoro-myo-inositol were actively concentrated. The monodeoxyfluoro-myo-inositols were also assayed for their ability to inhibit the uptake of myo-inositol into cells. Both 2-deoxy-2-fluoro-myo-inositol and 1D-3-deoxy-3-fluoro-myo-inositol were effective inhibitors of myo-inositol uptake. Furthermore, 1D-1-deoxy-1-fluoro-myo-inositol, which was not taken up actively, was an effective inhibitor of myo-inositol uptake. The three effective inhibitors all showed Ki values of approximately 150 microM, close to the apparent Km for inositol uptake of 180 microM, and the 4-, 5- and 6-fluoro analogues had Ki values in excess of 10 mM.

Animals↗
PubMed2001

Relationships of plasma C-peptide and gender to the urinary excretion of inositols in older people.

PURPOSE: The urinary excretions of myo-inositol and D-chiro-inositol are elevated in diabetes, and have been suggested as possible markers or effectors of insulin action. The aim of the present study was to measure the urinary excretion of these compounds, and to assess possible relationships with the metabolic control of glucose, in older, non-diabetic men and women. SUBJECTS: 32 older (age range 54-71 yrs), moderately overweight (body mass index 29.1 +/- 0.4 kg/m2, mean +/- SEM), non-diabetic men (n = 17) and women (n = 15). METHODS: 75 g oral glucose tolerance testing was done the day after all subjects had consumed nutrient-defined menus for five days. Plasma samples were analyzed for the concentrations of glucose, insulin, and C-peptide, and the 180-minute area under the curve (AUC) for each of these compounds was calculated. Samples from 24-hour urine collections were analyzed for the concentrations of myo-inositol, D-chiro-inositol, L-chiro-inositol, and pinitol. RESULTS: The fasting glucose, insulin, and C-peptide, and the AUC for glucose and insulin, were not different between men and women. C-peptide AUC was greater in the men versus the women (p < 0.001). The median urinary excretions (micromol/g creatinine) of myo-inositol (p < 0.001), D-chiro-inositol (p < 0.001), L-chiro-inositol (p < 0.05), and pinitol (p < 0.001) were higher, and the myo-inositol:D-chiro-inositol ratio was lower (p < 0.001), in the men versus women. For all subjects combined, C-peptide AUC was positively correlated with the urinary excretion of each of the measured inositols, as well as the myo-inositol:D-chiro-inositol ratio. The correlations between C-peptide AUC and these inositols were strongly influenced by the co-linear relationship between C-peptide AUC and gender. CONCLUSIONS: Collectively, these data show that older, moderately overweight, non-diabetic men and women with gender-related differences in glucose-stimulated C-peptide AUC, an indirect indicator of insulin secretion, also display differences in the urinary excretion of myo-inositol, D-chiro-inositol, L-chiro-inositol, and pinitol. The gender-related difference in the myo-inositol:D-chiro-inositol ratio suggests that, while the urinary excretion of all of the inositols measured were higher in the men than the women, the difference was more pronounced for D-chiro-inositol.

Aged↗
PubMed1987

Inositol 1,2-cyclic 4,5-trisphosphate is not a product of muscarinic receptor-stimulated phosphatidylinositol 4,5-bisphosphate hydrolysis in rat parotid glands.

We have employed a neutral-pH extraction technique to look for inositol 1,2-cyclic phosphate derivatives in [3H]inositol-labelled parotid gland slices stimulated with carbachol. The incubations were terminated by adding cold chloroform/methanol (1:2, v/v), the samples were dried under vacuum and inositol phosphates were extracted from the dried residues by phenol/chloroform/water partitioning. Water-soluble inositol metabolites were separated by h.p.l.c. at pH 3.7. 32P-labelled inositol phosphate standards (inositol 1-phosphate, inositol 1,2-cyclic phosphate, inositol 1,4,5-trisphosphate and inositol 1,2-cyclic 4,5-trisphosphate) were quantitively recovered through both extraction and chromatography steps. Treatment of inositol cyclic phosphate standards with 5% (w/v) HClO4 for 10 min prior to chromatography resulted in formation of the expected non-cyclic compounds. [3H]Inositol 1-phosphate and [3H]inositol 1,4,5-trisphosphate were both present in parotid gland slices and both increased during stimulation with 1 mM-carbachol. There was no evidence for significant quantities of [3H]inositol 1,2-cyclic phosphate or [3H]inositol 1,2-cyclic 4,5-trisphosphate in control or carbachol-stimulated glands. Parotid gland homogenates rapidly converted inositol 1,4,5-trisphosphate to inositol bisphosphate and inositol tetrakisphosphate, but metabolism of the inositol cyclic trisphosphate was much slower. The results suggest that inositol 1,4,5-trisphosphate, but not inositol 1,2-cyclic 4,5-trisphosphate, is the water-soluble product of muscarinic receptor-stimulated phospholipase C in rat parotid glands.

Animals↗
PubMed1988

L-myo-inositol 1,4,5,6-tetrakisphosphate is present in both mammalian and avian cells.

When myo-[3H]inositol-prelabelled primary-cultured murine bone-marrow-derived macrophages were challenged with platelet-activating factor (PAF; 200 ng/ml), there was a rapid (2.5-fold at 10 s) rise in the intracellular concentration of D-myo-[3H]inositol 1,4,5-trisphosphate, followed by a rise in myo-[3H]inositol tetrakisphosphate. myo-[3H]Inositol tetrakisphosphate fractions were isolated by high-performance anion-exchange chromatography from myo-[3H]inositol-prelabelled chick erythrocytes and primary-cultured macrophages. In both cases [3H]iditol and [3H]inositol were the only significant products (greater than 90% of recovered radioactivity) after oxidation to completion with periodic acid, reduction with NaBH4 and dephosphorylation with alkaline phosphatase. The presence of [3H]inositol after this procedure is consistent with the occurrence of [3H]inositol 1,3,4,5-tetrakisphosphate in the cell extracts, whereas [3H]iditol could only be derived from D- or L-inositol 1,4,5,6-tetrakisphosphate. When [3H]inositol tetrakisphosphate fractions obtained from (A) unstimulated macrophages, (B) macrophages that had been stimulated with PAF for 40s or (C) chick erythrocytes were subjected to the above procedure, radioactivity was recovered in these polyols in the following proportions: A, 60-90% in iditol, with 10-40% in inositol; B, total radioactivity increased by a factor of 9.8, 94% being recovered in inositol and 8% in iditol; C, 70-80% in iditol and 20-30% in inositol. [3H]Iditol derived from myo-[3H]inositol tetrakisphosphate fractions from macrophages and chick erythrocytes was oxidized to sorbose by L-iditol dehydrogenase (L-iditol:NAD+2-oxidoreductase, 1.1.1.14) at the same rate as authentic L-iditol. D-[14C]Iditol, derived from D-myo-inositol 1,4,5-trisphosphate, was not oxidized by L-iditol dehydrogenase. This result indicates that the [3H]iditol was derived from L-myo-inositol inositol 1,4,5,6-tetrakisphosphate. The data are consistent with rapid PAF-sensitive synthesis of D-myo-[3H]inositol 1,3,4,5-tetrakisphosphate in macrophages, and demonstrate that L-myo-inositol 1,4,5,6-tetrakisphosphate is synthesized in both mammalian and avian cells. The levels of L-myo-[3H]inositol 1,4,5,6-tetrakisphosphate in primary-cultured macrophages are not acutely sensitive to PAF.

Animals↗
PubMed1989

Inositol phospholipid metabolism during and following synaptic activation: role of adenosine.

The metabolic pathway of inositol phospholipids represents a series of synthetic and hydrolytic reactions with inositol as a by-product. Hence, the rate of [3H]inositol release from prelabeled phospholipids can be used as a reflection of activity of this pathway. In the frog sympathetic ganglion prelabeled with [3H]inositol, we studied the effect of synaptic activity (orthodromic stimulation) on release of 3H-label into the medium. This release was interpreted as [3H]inositol release. The value was low at rest and increased significantly by 32% during orthodromic stimulation (20 Hz for 5 min). However, on cessation of the stimulation, [3H]inositol release increased rapidly by 148% and remained elevated for at least 45 min. This increase in [3H]inositol release during and after the stimulation period was reduced by suffusion of the ganglia with adenosine. We hypothesized that synaptic activation releases a long-lasting stimulatory agonist and a short-lasting inhibitory (adenosine) agonist or agonists affecting [3H]inositol release. To demonstrate the presence of a stimulatory agonist, two sympathetic ganglia were used. One was prelabeled with [3H]inositol, and the other was not. The two ganglia were placed together in a 5-microliter droplet of Ringer's solution containing atropine. Orthodromic stimuli applied to the nonlabeled ganglion elicited release of [3H]inositol from the nonstimulated ganglion. To test whether the adenosine formed during orthodromic stimulation inhibits [3H]inositol release, we destroyed endogenous adenosine by suffusion of the ganglia with adenosine deaminase during the stimulation period. We found that adenosine deaminase induced large increases in [3H]inositol release during the stimulation period, in contrast to an increase seen only during the poststimulation period when adenosine deaminase was omitted. Because [3H]inositol release is assumed to parallel changes in content of inositol phosphates, we anticipated no changes of the levels of these compounds during orthodromic stimulation. However, measurements showed that levels of inositol phosphates and inositol phospholipids were all elevated except for phosphatidylinositol 4-phosphate. On termination of the stimulus, they remained elevated, with a further increase in levels of inositol trisphosphate and phosphatidylinositol 4-phosphate. We conclude that endogenous adenosine inhibits [3H]inositol release, possibly by modulating several of the steps of the inositol phospholipid pathway.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗
PubMed1986

Formation and metabolism of inositol 1,3,4,5-tetrakisphosphate in liver.

The inositol lipid pools of isolated rat hepatocytes were labeled with [3H]myo-inositol, stimulated maximally with vasopressin and the relative contents of [3H]inositol phosphates were measured by high performance liquid chromatography. Inositol 1,4,5-trisphosphate accumulated rapidly (peak 20 s), while inositol 1,3,4-trisphosphate and a novel inositol phosphate (ascribed to inositol 1,3,4,5-tetrakisphosphate) accumulated at a slower rate over 2 min. Incubation of hepatocytes with 10 mM Li+ prior to vasopressin addition selectively augmented the levels of inositol monophosphate, inositol 1,4-bisphosphate, and inositol 1,3,4-trisphosphate. A kinase was partially purified from liver and brain cortex which catalyzed an ATP-dependent phosphorylation of [3H]inositol 1,4,5-trisphosphate to inositol 1,3,4,5-tetrakisphosphate. Incubation of purified [3H]inositol 1,3,4,5-tetrakisphosphate with diluted liver homogenate produced initially inositol 1,3,4-trisphosphate and subsequently inositol 1,3-bisphosphate, the formation of which could be inhibited by Li+. The data demonstrate that the most probable pathway for the formation of inositol 1,3,4,5-tetrakisphosphate is by 3-phosphorylation of inositol 1,4,5-trisphosphate by a soluble mammalian kinase. Degradation of both compounds occurs first by a Li+-insensitive 5-phosphatase and subsequently by a Li+-sensitive 4-phosphatase. The prolonged accumulation of both inositol 1,4,5-trisphosphate and inositol 1,3,4,5-tetrakisphosphate in vasopressin-stimulated hepatocytes suggest that they have separate second messenger roles, perhaps both relating to Ca2+-signalling events.

Animals↗
PubMed1990

A myo-inositol D-3 hydroxykinase activity in Dictyostelium.

A soluble ATP-dependent enzyme which phosphorylates myo-inositol has been characterized in Dictyostelium. The myo-inositol kinase activity was partially purified from amoebae by chromatography on DEAE-Sepharose and phenyl-Sepharose columns. The product of both the partially purified activity and of a crude cytosolic fraction was myo-inositol 3-phosphate. The partially purified preparations of myo-inositol kinase (a) possessed a Km for myo-inositol of 120 microM (in the presence of 5 mM-ATP) and for ATP of 125 microM (in the presence of 1 microM-myo-inositol), (b) did not recognize allo-, epi-, muco-, neo-, scyllo-, 1 D-chiro or 1 L-chiro-inositol as substrates, (c) were competitively inhibited by three naturally occurring analogues of myo-inositol: 1 L-chiro-inositol (Ki 49.5 +/- 0.7 microM: the structural equivalent of myo-inositol, except that the D-3 hydroxy moiety is axial), D-3-deoxy-myo-inositol [Ki 103 +/- 1 microM: (-)-viburnitol], and sequoyitol (Ki 271 +/- 7 microM; unlike 1 L-chiro-inositol and D-3-deoxy-myo-inositol, this was a substrate for the kinase), and finally (d) were apparently non-competitively inhibited by myo-inositol 3-phosphate. The product of myo-inositol kinase could be detected in intact amoebae and was a substrate for the first in a series of inositol polyphosphate kinases present in Dictyostelium which ultimately yield myo-inositol hexakisphosphate. The activity of myo-inositol D-3-hydroxykinase in Dictyostelium lysates showed evidence of developmental regulation.

Carbon Radioisotopes↗
PubMed1988

Multiple pathways of inositol polyphosphate metabolism in angiotensin-stimulated adrenal glomerulosa cells.

The production and metabolism of inositol 1,4,5-trisphosphate (Ins-1,4,5-P3) and other inositol polyphosphates was studied in cultured bovine adrenal glomerulosa cells prelabeled for 24 h with [3H]inositol. During stimulation with angiotensin II, Ins-1,4,5-P3 increased to a peak of 15-fold above basal within 10 s, followed by a second phase of continuous increase over the next 30 min. Ins-1,4,5-P3 formed during agonist stimulation was rapidly metabolized by two distinct pathways. The more direct metabolic route was via degradation by sequential dephosphorylations to form inositol 1,4-bisphosphate and inositol 4-phosphate, and ultimately inositol. Lithium ions inhibited both the formation and dephosphorylation of inositol 4-monophosphate, which is a specific product of inositol polyphosphate metabolism. In addition, a cyclical metabolic sequence was initiated by the 3-phosphorylation of Ins-1,4,5-P3 to form inositol 1,3,4,5-tetrakisphosphate. The Ins-1,4,5-P3 3-kinase responsible for this reaction had a Km of 0.4 microM for Ins-1,4,5-P3 and a Vmax of 208 pmol/min/mg and was stimulated by increased Ca2+ concentrations in the micromolar range. Inositol 1,3,4,5-tetrakisphosphate was then dephosphorylated to inositol 1,3,4-trisphosphate, which in turn was either further degraded to inositol 3,4-bisphosphate or rephosphorylated to inositol 1,3,4,6-tetrakisphosphate. Lithium ions also inhibited the production of inositol 3,4-bisphosphate, explaining the large accumulation of inositol 1,3,4-trisphosphate in cells stimulated in the presence of lithium. Prolonged exposure to angiotensin II in the presence of Li+ caused a progressive decline in inositol polyphosphate formation without depletion of the lipid precursor, phosphatidyl-inositol 4,5-bisphosphate, suggesting that an accumulating product of polyphosphoinositide hydrolysis (possibly diacylglycerol) has an inhibitory effect on the phospholipase C-catalyzed breakdown process. These results indicate that, in addition to its breakdown by sequential dephosphorylations through Ins-1,4-P2 and Ins-4-P, Ins-1,4,5-P3 undergoes a complex series of phosphorylations and dephosphorylations to form at least two inositol tetrakisphosphates and their metabolites. These newly defined pathways may provide additional regulatory steps in the mechanism of cell activation by angiotensin II and other Ca2+-mobilizing hormones.

Adrenal Cortex↗
PubMed1993

Lithium increases accumulation of second messenger inositol 1,4,5-trisphosphate in brain cortex slices in species ranging from mouse to monkey.

Historical aspects of the phosphoinositide field are briefly reviewed. The effects of the anti-manic depressive drug, lithium, on inositol 1,4,5-trisphosphate accumulation in brain cortex slices in species ranging from mouse to monkey are presented. In the guinea pig, lithium, in the presence of acetylcholine, increases the accumulation of inositol 1,4,5-trisphosphate and inositol 1,3,4,5-tetrakisphosphate, but at therapeutic concentrations of lithium 1 mM inositol is required to see a statistically significant effect. In previous studies in rat brain cortex slices, lithium inhibited accumulation of inositol 1,4,5-trisphosphate by 15-20%. We have confirmed this and found a similar effect in mouse brain cortex slices. However, if we added 20-30 mM inositol we observed lithium-stimulated accumulations of inositol 1,4,5-trisphosphate and inositol 1,3,4,5-tetrakisphosphate in these two latter species. These observations in rat and mouse appear to relate to the following facts: (1) brain cortices of mouse and rat contain in vivo concentrations of inositol half that of guinea pig, (2) incubated rat brain cortex slices are depleted of inositol by 80% and (3) the slices require 10 mM inositol supplementation to restore in vivo concentrations. More recently, we have shown that in monkey brain cortex slices, therapeutic concentrations of Li+ increase accumulation of inositol 1,4,5-trisphosphate. Inositol 1,3,4,5-tetrakisphosphate is not increased. Neither inositol, nor an agonist, is required. The same effects are seen whether inositol 1,4,5-trisphosphate is measured by the [3H]inositol-prelabelling technique or by mass assay, although mass includes a pool of inositol 1,4,5-trisphosphate which is metabolically inactive. Thus, in a therapeutically relevant model for man, Li+ increases Ins(1,4,5)P3 in brain cortex slices, as was previously seen in lower mammals at nonrate-limiting concentrations of inositol.

Animals↗
PubMed1997

Controlled trials of inositol in psychiatry.

Inositol is a simple polyol precursor in a second messenger system important in the brain. Cerebrospinal fluid inositol has been reported as decreased in depression. A double-blind controlled trial of 12 g daily of inositol in 28 depressed patients for four weeks was performed. Significant overall benefit for inositol compared to placebo was found at week 4 on the Hamilton Depression Scale. No changes were noted in hematology, kidney or liver function. Since many antidepressants are effective in panic disorder, twenty-one patients with panic disorder with or without agoraphobia completed a double-blind, placebo-controlled, four week, random-assignment crossover treatment trial of inositol 12 g per day. Frequency and severity of panic attacks and severity of agoraphobia declined significantly with inositol compared to placebo. Side-effects were minimal. Since serotonin re-uptake inhibitors benefit obsessive compulsive disorder (OCD) and inositol is reported to reverse desensitization of serotonin receptors, thirteen patients with OCD completed a double-blind controlled crossover trial of 18 g inositol or placebo for six weeks each. Inositol significantly reduced scores of OCD symptoms compared with placebo. A controlled double-blind crossover trial of 12 g daily of inositol for a month in twelve anergic schizophrenic patients, did not show any beneficial effects. A double-blind controlled crossover trial of 6 g of inositol daily vs. glucose for one month each was carried out in eleven Alzheimer patients, with on clearly significant therapeutic effects. Antidepressant drugs have been reported to improve attention deficit disorder (ADDH) with hyperactivity symptomatology. We studied oral inositol in children with ADDH in a double-blind, crossover, placebo-controlled manner. Eleven children, mean age 8.9 +/- 3.6 years were enrolled in an eight week trial of inositol or placebo at a dose of 200 mg/kg body weight. Results show a trend for aggravation of the syndrome with myo-inositol as compared to placebo. Recent studies suggest that serotonin re-uptake inhibitors are helpful in at least some symptoms of autism. However a controlled double-blind crossover trial of inositol 200 mg/kg per day showed no benefit in nine children with autism. Cholinergic agonists have been reported to ameliorate electroconvulsive therapy (ECT)-induced memory impairment. Inositol metabolism is involved in the second messenger system for several muscarinic cholinergic receptors. Inositol 6 g daily was given in a crossover-double-blind manner for five days before the fifth or sixth ECT to a series of twelve patients, without effect. These results suggest that inositol has therapeutic effects in the spectrum of illness responsive to serotonin selective re-uptake inhibitors, including depression, panic and OCD, and is not beneficial in schizophrenia, Alzheimer's ADDH, autism or ECT-induced cognitive impairment.

Adult↗
PubMed1990

myo-inositol metabolites as cellular signals.

The discovery of the second-messenger functions of inositol 1,4,5-trisphosphate and diacylglycerol, the products of hormone-stimulated inositol phospholipid hydrolysis, marked a turning point in studies of hormone function. This review focuses on the myo-inositol moiety which is involved in an increasingly complex network of metabolic interconversions, myo-Inositol metabolites identified in eukaryotic cells include at least six glycerophospholipid isomers and some 25 distinct inositol phosphates which differ in the number and distribution of phosphate groups around the inositol ring. This apparent complexity can be simplified by assigning groups of myo-inositol metabolites to distinct functional compartments. For example, the phosphatidylinositol 4-kinase pathway functions to generate inositol phospholipids that are substrates for hormone-sensitive forms of inositol-phospholipid phospholipase C, whilst the newly discovered phosphatidylinositol 3-kinase pathway generates lipids that are resistant to such enzymes and may function directly as novel mitogenic signals. Inositol phosphate metabolism functions to terminate the second-messenger activity of inositol 1,4,5-trisphosphate, to recycle the latter's myo-inositol moiety and, perhaps, to generate additional signal molecules such as inositol 1,3,4,5-tetrakisphosphate, inositol pentakisphosphate and inositol hexakisphosphate. In addition to providing a more complete picture of the pathways of myo-inositol metabolism, recent studies have made rapid progress in understanding the molecular basis underlying hormonal stimulation of inositol-phospholipid-specific phospholipase C and inositol 1,4,5-trisphosphate-mediated Ca2+ mobilisation.

1-Phosphatidylinositol 4-Kinase↗
PubMed1991

Restoration of Na(+)-K+ pump activity and resting membrane potential by myo-inositol supplementation in neuroblastoma cells chronically exposed to glucose or galactose.

myo-Inositol uptake by culture neuroblastoma cells at a concentration of myo-inositol less than 50 microM was largely Na+ dependent. Exposing neuroblastoma cells to media supplemented with increasing concentrations of myo-inositol resulted in an increase in myo-inositol accumulation and intracellular content, but myo-inositol incorporation into phospholipids was not increased. The data indicate that myo-inositol exists as separate pools in neuroblastoma cells, and one or more of these pools may contribute to phospholipid synthesis. Exposing neuroblastoma cells to an increased concentration of glucose caused a decrease in myo-inositol uptake by two separate mechanisms. Acute exposure of the cells to 30 mM glucose caused a myo-inositol concentration-dependent decrease in Na(+)-dependent myo-inositol uptake. We propose that the acute inhibition of myo-inositol uptake by glucose is likely due to a competitive type of inhibition. Chronic exposure of cells to media containing 30 mM glucose or 30 mM galactose also caused decreases in myo-inositol uptake and incorporation into inositol phospholipids and intracellular myo-inositol content. This decrease in myo-inositol metabolism persisted at a higher concentration of external myo-inositol than the acute inhibition. Supplementing media containing 30 mM glucose or 30 mM galactose with 250 microM myo-inositol restored myo-inositol metabolism and content. The inhibition of myo-inositol uptake by cells chronically exposed to increased concentrations of glucose or galactose was due to a noncompetitive type of inhibition that was blocked by the addition of sorbinil. Chronic exposure of neuroblastoma cells to media containing 30 mM glucose or 30 mM galactose caused a decrease in Na(+)-K(+)-ATPase transport activity and resting membrane potential.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1982

Myo-inositol homeostasis in foetal rabbit lung.

In several species, lung maturation is accompanied by a decline in the phosphatidylinositol content of lung surfactant and a concomitant increase in its phosphatidylglycerol content. To examine the possibility that this developmental change is influenced by the availability of myo-inositol, potential sources of myo-inositol for the developing rabbit lung were investigated. On day 28 of gestation the myo-inositol content of foetal rabbit lung tissue (2.3+/-0.5mumol/g of tissue) was not significantly different from that of adult lung tissue but the activity of d-glucose 6-phosphate:1l-myo-inositol 1-phosphate cyclase (cyclase) in foetal lung tissue (81.0+/-9.0nmol.h(-1).g of tissue(-1)) was higher than that found in adult lung tissue (23.2+/-1.0nmol.h(-1).g of tissue(-1)). Day 28 foetal rabbit lung tissue was found also to take up myo-inositol by a specific, energy-dependent, Na(+)-requiring mechanism. Half-maximal uptake of myo-inositol by foetal rabbit lung slices was observed when the concentration of myo-inositol in the incubation medium was 85mum. When the myo-inositol concentration was 1mm (but not 100mum) the addition of glucose (5.5mm) stimulated myo-inositol uptake. myo-Inositol uptake was observed also in adult rabbit lung and was found to be sub-maximal at the concentration of myo-inositol found in adult rabbit serum. The concentration of myo-inositol in the serum of pregnant adult rabbits (47.5+/-5.5mum) was significantly lower than that of non-pregnant adult female rabbits (77.9+/-9.2mum). On day 28 of gestation the concentration of myo-inositol in foetal serum (175.1+/-12.0mum) was much less than on day 25, but more than that found on day 30. A transient post-partum increase in the concentration of myo-inositol in serum was followed by a rapid decline. Much of the myo-inositol in foetal rabbit serum probably originates from the placenta, where on day 28 of gestation a high cyclase activity (527+/-64nmol.h(-1).g of tissue(-1)) was measured. The gestational decline in serum myo-inositol concentration, together with the decreasing cyclase activity of the lungs, is consistent with the view that maturation of the lungs is accompanied by decreased availability of myo-inositol to this tissue.

Animals↗
PubMed1991

Perinatal development of inositol synthesis and catabolism in rabbit kidney.

Inositol influences growth and perinatal development. To investigate the causes of the decrease in serum inositol levels during perinatal development, the rate-limiting enzyme activities in the catabolism and synthesis of inositol, inositol oxygenase and glucose-6-phosphate:L-inositol-1-phosphate cyclase (cyclase) were measured. The specific activity of inositol oxygenase (uniquely present in the kidney) increased 18-fold between the 25th fetal and the 17th neonatal days, and, at the same time, the specific activity of cyclase decreased by 50%. Between cortex and medulla, there were striking differences in the distribution of inositol oxygenase, when compared to the distribution of both cyclase and free inositol. Inositol supplementation during pregnancy increased serum inositol both in the doe and the fetuses, and tended to increase the inositol concentration in organs with relatively low cyclase activity and low free inositol (liver, lung). An acute oral inositol load and/or glucocorticoid intramuscularly is administered to the pregnant doe did not alter either maternal or fetal inositol oxygenase activities. It is proposed that the tissue contents of inositol are in part regulated by the rate of the endogenous synthesis. The development of inositol oxygenase activity may influence serum inositol concentrations during the perinatal period, in addition to the diet.

Aging↗
PubMed1998

Dietary myo-inositol therapy in hyperglycemia-induced embryopathy.

Dysmorphogenesis in diabetic mothers occurs more frequently than in the general population. This phenomenon is believed to be caused by the teratogenic effects of metabolic fuel mixtures with associated membrane injury and aberrations in the biochemical constituents. The present experiment was designed to determine: 1) if hyperglycemia-induced membrane injury is associated with intracellular and/or extracellular lipid disturbances; 2) if supplemental myo-inositol therapy prevents hyperglycemia-induced embryopathy; 3) if a correlation exists between dietary myo-inositol, serum and tissue levels of myo-inositol, and conceptus development; and 4) the cellular content of arachidonic acid following myo-inositol supplementation. Sixty-five female Sprague-Dawley rats were mated, and divided into three groups. One group was nondiabetic normal controls, and two groups had diabetes experimentally induced with streptozotocin. Of the diabetic groups, one received a normal diet, while the other received a myo-inositol-supplemented diet during the period of organogenesis. Blood samples were collected on days 0 and 12 of pregnancy. Embryos and yolk sacs were analyzed for myo-inositol and arachidonic acid levels, using mass spectrochromatography. Dietary myo-inositol supplementation of diabetic mothers resulted in a significant decrease in the incidence of neural tube defects when compared with diabetics not receiving supplements (9.5 vs. 20.4%; P < 0.05). This protective effect was incomplete, based on the incidence observed in the nondiabetic controls (9.5 vs. 3.8%; P < 0.05). The myo-inositol embryonic tissue levels in the diabetic group which had been fed a regular diet without supplementation were significantly lower than in the nondiabetic group. Dietary therapy successfully restored myo-inositol levels in the yolk sacs, as suggested by similar tissue levels in diabetics receiving myo-inositol supplementation and normal controls (18.7 +/- 1.3 vs. 19.1 +/- 2.0 ng/mg; P = ns). Dietary therapy, however, failed to restore myo-inositol levels in the embryos, suggesting hyperglycemia-induced faulty transport of nutrients from the yolk sac to the embryo. No correlation was noted between maternal blood levels of myo-inositol, with or without supplementation, and the clinical outcome. Tissue arachidonic acid levels were markedly reduced in the conceptuses of diabetic mothers with (0.4 +/- 0.1 micrograms/mg) or without (0.25 +/- 0.08 micrograms/mg) myo-inositol supplementation when compared to the nondiabetic controls (3.33 +/- 0.24 micrograms/mg). These data demonstrate that diabetes-induced embryopathy is associated with a deficiency state in both myo-inositol and arachidonic acid. The myo-inositol deficiency is not demonstrated at the serum level, but rather at the tissue level, suggesting a paracrine action. Dietary supplementation of myo-inositol is associated with an increase in tissue myo-inositol levels and a decrease in malformations. This therapy holds promise for use as a dietary prophylaxis against diabetic embryopathy.

Animals↗