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PubMed1988

Calcium modulates the generation of inositol 1,3,4-trisphosphate in human platelets by the activation of inositol 1,4,5-trisphosphate 3-kinase.

We observed that more total inositol trisphosphate (InsP3) was formed when human platelets were stimulated with agonists (15-hydroxy-9,11-azo-prosta-5,13-dienoic acid or thrombin) in the presence of extracellular Ca2+ than in its absence. Analysis of the InsP3 by h.p.l.c. indicated that the increased InsP3 formed in the presence of extracellular Ca2+ was primarily the 1,3,4-trisphosphate [Ins(1,3,4)P3]. In addition, more inositol 1,3,4,5-tetrakisphosphate (InsP4) was formed in the presence of extracellular Ca2+. Experiments conducted with electrically permeabilized platelets demonstrated that conversion of [3H]Ins(1,4,5)P3 to [3H]InsP4 in platelets was Ca2+-dependent, with half-maximal conversion observed at approx. 2.5 microM-Ca2+. By contrast, dephosphorylation of [3H]InsP4 to [3H]Ins(1,3,4)P3 was not activated by Ca2+. A partially purified preparation of Ins(1,4,5)P3 3-kinase from human platelets was found to be insensitive to Ca2+, but addition of calmodulin restored Ca2+-sensitivity to the kinase, increasing its activity about 5-fold. These results show that in human platelets the metabolism of Ins(1,4,5)P3 is regulated by Ca2+-calmodulin, and suggest that the metabolites of Ins(1,4,5)P3 may also have important second-messenger functions in platelets, and are consistent with the hypothesis that the activation of phospholipase C is not dependent on extracellular Ca2+.

Blood Platelets↗
PubMed1990

Inositol 1,3,4,5-tetrakisphosphate stimulates calcium release from bovine adrenal microsomes by a mechanism independent of the inositol 1,4,5-trisphosphate receptor.

In bovine adrenal microsomes, Ins(1,4,5)P3 binds to a specific high-affinity receptor site (Kd = 11 nM) with low affinity for two other InsP3 isomers, Ins(1,3,4)P3 and Ins(2,4,5)P3. In the same subcellular fractions Ins(1,4,5)P3 was also the most potent stimulus of Ca2+ release of all the inositol phosphates tested. Of the many inositol phosphates recently identified in angiotensin-II-stimulated adrenal glomerulosa and other cells, Ins(1,3,4,5)P4 has been implicated as an additional second messenger that may act in conjunction with Ins(1,4,5)P3 to elicit Ca2+ mobilization. In the present study, an independent action of Ins(1,3,4,5)P4 was observed in bovine adrenal microsomes. Heparin, a sulphated polysaccharide which binds to Ins(1,4,5)P3 receptors in several tissues, inhibited both the binding of radiolabelled Ins(1,4,5)P3 and its Ca2(+)-releasing activity in adrenal microsomes. In contrast, heparin did not inhibit the mobilization of Ca2+ by Ins(1,3,4,5)P4, even at doses that abolished the Ins(1,4,5)P3 response. Such differential inhibition of the Ins(1,4,5)P3- and Ins(1,3,4,5)P4-induced Ca2+ responses by heparin indicates that Ins(1,3,4,5)P4 stimulates the release of Ca2+ from a discrete intracellular store, and exerts this action via a specific receptor site that is distinct from the Ins(1,4,5)P3 receptor.

Adrenal Glands↗
PubMed1991

A high-affinity inositol 1,3,4,5-tetrakisphosphate receptor protein from brain is specifically labelled by a newly synthesized photoaffinity analogue, N-(4-azidosalicyl)aminoethanol(1)-1-phospho-D-myo-inositol 3,4,5-trisphosphate.

A photolabile arylazido analogue of Ins(1,3,4,5)P4 selectively substituted at the 1-phosphate group was synthesized by coupling 2-aminoethanol(1)-1-phospho-D-myo-inositol 4,5-bisphosphate with N-hydroxysuccinimidyl-4-azidosalicylic acid [Schäfer, Nehls-Sahabandu, Grabowsky, Dehlinger-Kremer, Schulz & Mayr (1990) Biochem. J. 272, 817-825] and subsequently phosphorylating the product by bovine brain Ins(1,4,5)P3 3-kinase. The product, N-(4-azidosalicyl)-aminoethanol(1)-1-phospho-D-myo-inositol 3,4,5-trisphosphate [AsaIns(1,3,4,5)P4] was radioiodinated and purified by anion-exchange chromatography. AsaIns(1,3,4,5)P4 bound to a high-affinity Ins(1,3,4,5)P4 receptor from pig cerebellum with an affinity only 3-fold lower than that of Ins(1,3,4,5)P4. Photoirradiation of 125I-AsaIns(1,3,4,5)P4 in the presence of the receptor preparation revealed that the radioactive label was specifically associated with a protein band of apparent molecular mass 42 kDa, which Donié & Reiser [(1991) Biochem. J. 275, 453-457] had previously tentatively assigned to the Ins(1,3,4,5)P4 receptor protein. The radioactive label was displaced from the receptor when the binding reaction with 125I-AsaIns(1,3,4,5)P4 was carried out in the presence of 5 microM-Ins(1,3,4,5)P4.

Affinity Labels↗
PubMed1994

Inositol 1,3,4,5-tetrakisphosphate-gated channels interact with inositol 1,4,5-trisphosphate-gated channels in olfactory receptor neurons.

Inositol 1,4,5-trisphosphate [InsP3(1,4,5)] is a major second messenger regulating Ca2+ signaling in excitable and nonexcitable cells. InsP3(1,4,5) is extensively metabolized through a network of phosphorylation and dephosphorylation steps to products with potential second messenger function. Inositol 1,3,4,5-tetrakisphosphate [InsP4(1,3,4,5)], the direct metabolite of InsP3(1,4,5), has also been associated with Ca2+ signaling, but whether InsP4(1,3,4,5) acts in combination with InsP3(1,4,5) or whether it regulates Ca2+ signaling directly and independently is unclear, particularly in neurons. We report that olfactory receptor neurons in the lobster (Panulirus argus) express an InsP4(1,3,4,5) receptor in the plasma membrane that is a functional channel. The channel differs in conductance, kinetics, and voltage sensitivity from two plasma membrane InsP3(1,4,5)-gated channels previously reported in these neurons. In close spatial proximity, the InsP4(1,3,4,5)-and InsP3(1,4,5)-gated channels interact reciprocally to alter the channels' open probabilities in what may be a novel mechanism for regulating Ca2+ entry in neurons.

Animals↗
PubMed1991

Inositol tetrakisphosphate liberates stored Ca2+ in Xenopus oocytes and facilitates responses to inositol trisphosphate.

1. The actions of the putative second messenger inositol 1,3,4,5-tetrakisphosphate (Ins(1,3,4,5)P4) were studied by injecting it into voltage-clamped oocytes while recording Ca(2+)-dependent chloride membrane currents and, in some experiments, fluorescence signals from Ca2+ indicators. 2. Ins(1,3,4,5)P4 evoked a rise in intracellular Ca2+ and associated chloride current in oocytes bathed in normal or Ca(2+)-free Ringer solutions. The fluorescence Ca2+ signal showed a prolonged rise with superimposed oscillations, whereas the current reflected only the oscillatory component. 3. Injections of inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) evoked currents showing an initial transient, followed by oscillations. Ins(1,3,4,5)P4 evoked similar oscillations, but the transient component was usually small or absent. Ins(1,3,4,5)P4 was about 20-fold less potent than Ins(1,4,5)P3, as measured by comparing doses required to elicit currents with the same integral. The most sensitive oocytes responded to about 1 fmol Ins(1,3,4,5)P4 and 0.1 fmol Ins(1,4,5)P3. 4. Injections of Ins(2,4,5)P4 evoked oscillatory currents, with a potency about three times greater than Ins(1,4,5)P3. Ins(1,3,4)P4 was ineffective in some oocytes even at doses of several picomoles, but in other oocytes evoked small transient and oscillatory currents with a potency 100 times or more less than Ins(1,3,4,5)P4. 5. Injections of Ins(1,3,4,5)P4 made into the animal hemisphere of the oocyte evoked larger currents than injections into the vegetal hemisphere. 6. Photo-release of Ins(1,4,5)P3 from caged Ins(1,4,5)P4 loaded into the oocyte was used to examine interactions between Ins(1,4,5)P3 and Ins(1,3,4,5)P4. Injection of low (ca 1 fmol) doses of Ins(1,3,4,5)P4 shortly before a light flash greatly facilitated currents evoked by photo-release of near-threshold amounts of Ins(1,4,5)P3. This facilitation was unaffected by removal of extracellular Ca2+ and arose because Ins(1,3,4,5)P4 reduced the threshold amount of Ins(1,4,5)P3 required to evoke a response. 7. Larger amounts (several femtomoles) of Ins(1,3,4,5)P4 depressed responses evoked by photo-release of Ins(1,4,5)P3. This may arise because Ca2+ liberated by Ins(1,3,4,5)P4 inhibits the ability of Ins(1,4,5)P3 to release further Ca2+. 8. We conclude that Ins(1,3,4,5)P4 liberates intracellular Ca2+ in the oocyte in a manner similar to that of Ins(1,4,5)P3, and suggest that a physiological role for Ins(1,3,4,5)P4 may be to facilitate responses to Ins(1,4,5)P3.

Animals↗
PubMed2005

Pretreatment with D-myo-inositol trisphosphate reduces infarct size in rabbit hearts: role of inositol trisphosphate receptors and gap junctions in triggering protection.

Pretreatment with D-myo-inositol-1,4,5-trisphosphate hexasodium (D-myo-IP(3)), the sodium salt of the second messenger inositol 1,4,5-trisphosphate (IP(3)), is cardioprotective and triggers a reduction of infarct size comparable in magnitude to that obtained with ischemic preconditioning. However, this observation is enigmatic; whereas IP(3) signaling is conventionally initiated by receptor binding, IP(3) receptors are typically considered to be intracellular, and D-myo-IP(3) is membrane-impermeable. We propose that this paradox is explained by the presence of poorly characterized external IP(3) receptors and hypothesize that: 1) infarct size reduction with D-myo-IP(3) is receptor-mediated; and 2) communication via gap junctions and/or hemichannels is required to initiate this protection. To investigate the role of receptor binding, isolated buffer-perfused rabbit hearts underwent 30 min of coronary occlusion (CO) and 2 h of reflow. Prior to CO, hearts received no treatment (controls), D-myo-IP(3), L-myo-IP(3) (enantiomer not recognized by the IP(3) receptor), D-myo-IP(3) + the IP(3) receptor inhibitor xestospongin C (XeC), or XeC alone. Infarct size, assessed by tetrazolium staining, was reduced with D-myo-IP(3) treatment, whereas hearts that received L-myo-IP(3) or D-myo-IP(3) + XeC showed no protection. To evaluate the contribution of gap junctions/hemichannels, additional control and D-myo-IP(3)-treated cohorts received a 5-min infusion of heptanol or Gap 27, two structurally distinct gap junction inhibitors, administered at doses confirmed to attenuate intercellular transmission of a gap junction-permeable fluorescent dye. There was no infarct-sparing effect of D-myo-IP(3) in inhibitor-treated hearts. These data support the concepts that infarct size reduction with D-myo-IP(3) is triggered by receptor binding and that communication via gap junctions/hemichannels is involved in initiating this protection.

Animals↗
PubMedDate not supplied

Regulation of inositol 1,4,5-trisphosphate-induced calcium release by inositol 1,4,5-trisphosphate and calcium in human platelets.

Inositol 1,4,5-trisphosphate (IP3)-induced release of Ca2+, its regulation by IP3 and Ca2+, and the metabolism of IP3 was analyzed in saponin-permeabilized human platelets. At 37 degrees C successive sub-maximal aliquots of IP3 induce a biphasic release of part of the IP3-sensitive Ca2+ pool each time. Although the IP3-induced Ca2+ flux rapidly ceases after addition of IP3, the IP3-sensitive Ca2+ stores regain their sensitivity shortly after stimulation with IP3. Under these conditions IP3 is rapidly hydrolyzed to inositol 1,4-bisphosphate which is unable to release Ca2+. The cooperativity of IP3-induced Ca2+ release and the metabolism of IP3 can account for both the rapid recovery of sensitivity of the IP3-sensitive Ca2+ pool and the partial release induced by sub-maximal concentrations of IP3. The data of the present study favour a steady state rather than an all-or-none mechanism of Ca2+ release.

Aniline Compounds↗
PubMed1991

Bradykinin-induced Ca(2+)-influx into cultured aortic endothelial cells is not regulated by inositol 1,4,5-trisphosphate or inositol 1,3,4,5-tetrakisphosphate.

Since inositol 1,4,5-trisphosphate (1,4,5-IP3) and inositol 1,3,4,5-tetrakisphosphate (1,3,4,5-IP4) have been described to modulate Ca(2+)-channels, we investigated the possible participation of 1,4,5-IP3 and/or 1,3,4,5-IP4 in the bradykinin-induced Ca(2+)-influx into cultured porcine aortic endothelial cells. In our experiments bradykinin induced a quick release of Ca2+ from intracellular stores and a longlasting Ca(2+)-influx, which remained constant for at least 15 minutes. In contrast to its effect on [Ca2+]i, bradykinin only transiently elevated 1,4,5-IP3 and 1,3,4,5-IP4 levels. Ten minutes after addition of bradykinin, both 1,4,5-IP3 and 1,3,4,5-IP4 levels returned to basal values, whereas Ca(2+)-influx was still unaltered. Furthermore, preincubation of endothelial cell with phorbol-12-myristate-13-acetate (PMA) abolished the stimulatory effect of bradykinin on the formation of 1,4,5-IP3 and 1,3,4,5-IP4, but did not affect the longlasting Ca(2+)-influx. These data provide evidence that in endothelial cells inositolphosphates are not involved in the regulation of bradykinin-induced longlasting Ca(2+)-influx.

Animals↗
PubMed1988

Characterization of inositol 1,4,5-trisphosphate-stimulated calcium release from rat cerebellar microsomal fractions. Comparison with [3H]inositol 1,4,5-trisphosphate binding.

The abilities of D-myo-inositol phosphates (InsPs) to promote Ca2+ release and to compete for D-myo-[3H]-inositol 1,4,5-trisphosphate [( 3H]Ins(1,4,5)P3) binding were examined with microsomal preparations from rat cerebellum. Of the seven InsPs examined, only Ins(1,4,5)P3, Ins(2,4,5)P3 and Ins(4,5)P2 stimulated the release of Ca2+. Ca2+ release was maximal in 4-6 s and was followed by a rapid re-accumulation of Ca2+ into the Ins(1,4,5)P3-sensitive compartment after Ins(1,4,5)P3, but not after Ins(2,4,5)P3 or Ins(4,5)P2. Ca2+ re-accumulation after Ins(1,4,5)P3 was also faster than after pulse additions of Ca2+, and coincided with the metabolism of [3H]Ins(1,4,5)P3. These data suggest that Ins(1,4,5)P3-induced Ca2+ release and the accompanying decrease in intraluminal Ca2+ stimulate the Ca2+ pump associated with the Ins(1,4,5)P3-sensitive compartment. That this effect was observed only after Ins(1,4,5)P3 may reflect differences in either the metabolic rates of the various InsPs or an effect of the Ins(1,4,5)P3 metabolite Ins(1,3,4,5)P4 to stimulate refilling of the Ins(1,4,5)P3-sensitive store. InsP-induced Ca2+ release was concentration-dependent, with EC50 values (concn. giving half-maximal release) of 60, 800 and 6500 nM for Ins(1,4,5)P3, Ins(2,4,5)P3 and Ins(4,5)P2 respectively. Ins(1,4,5)P3, Ins(2,4,5)P3 and Ins(4,5)P2 also competed for [3H]Ins(1,4,5)P3 binding, with respective IC50 values (concn. giving 50% inhibition) of 100, 850 and 13,000 nM. Comparison of the EC50 and IC50 values yielded a significant correlation (r = 0.991). These data provide evidence of an association between the [3H]Ins(1,4,5)P3-binding site and the receptor mediating Ins(1,4,5)P3-induced Ca2+ release.

Animals↗
PubMed1994

Synthesis and investigation of the possible insulin-like activity of 1D-4-O- and 1D-6-O-(2-amino-2-deoxy-alpha-D-glucopyranosyl)-myo-inositol 1-phosphate and 1D-6-O-(2-amino-2-deoxy-alpha-D-glucopyranosyl)-myo-inositol 1,2-(cyclic phosphate).

The synthesis of the glycosyl-myo-inositol 1-phosphates 1 and 2 and of the glycosyl-myo-inositol 1,2-(cyclic phosphate) 3, starting from previously synthesized intermediates, is reported. Compound 3 was found to display proliferative effects on the early developing inner ear of chick embryo.

Animals↗
PubMed1990

Synthesis of phosphonate derivatives of myo-inositol for use in biochemical studies of inositol-binding proteins.

Phospholipids containing the inositol headgroup (phosphoinositides) serve as membrane storage forms of a family of messenger molecules that transmit signals in cells. In this study a general synthesis of myo-inositol phosphate derivatives in which the phosphorus oxygen bond is replaced with a phosphorus carbon bond (i.e. phosphonates) is presented. Four specific examples of phosphonate analogs of phosphatidylinositol (PI) are prepared which have a single alkyl chain in place of the diacylglycerol. These derivatives are stable in neutral and alkaline solutions and are designed for use in biochemical studies of PI-specific phospholipases C and other enzymes involved in the phosphoinositide signal transduction pathway.

Chemical Phenomena↗
PubMed1994

Time course of formation of inositol phosphates during enzymatic hydrolysis of phytic acid (myo-inositol hexaphosphoric acid) by phytase determined by capillary isotachophoresis.

Capillary isotachophoresis with conductivity detection was applied to the investigation of the hydrolytic decomposition of phytic acid (myo-inositol hexaphosphoric acid) by phytase, and for the formation of the reaction products as a function of time. The quantitation of all analytes (besides phytic acid the mono- to penta-phosphorylated inositols and orthophosphate) can be carried out using two different buffer systems.

6-Phytase↗
PubMedDate not supplied

Ageing of Neurospora crassa. III. Induction of cellular death and clonal senescence of an inositol-less mutant by inositol starvation and the protective effect of dietary antioxidants.

Clonal growth rate and cellular viability of an inositol-less mutant of Neurospora crassa decline rapidly during deprivation of dietary inositol. Dietary antioxidants, either nordihydroguaiaretic acid, vitamin E or 3,5-ditert.-butyl-4-hydroxybenzyl alcohol, protected cells and clones of the mutant from death and senescence. Membrane deterioration with associated lipid autoxidation and consequent deleterious free radical reactions appear to be, in part at least, the causes of the mutant's death and senescence.

Antioxidants↗
PubMed1990

Ca2(+)-dependence provides evidence for differing mechanisms of GABA-induced inositol phosphate formation and GABA potentiation of inositol phosphate formation induced by noradrenaline in rat cerebral cortex.

[3H]Inositol phosphate formation ([3H]IP) induced by gamma-aminobutyric acid (GABA) in slices of rat cerebral cortex prelabelled with [3H]inositol was abolished in Krebs-Henseleit medium without added Ca2+, but could be restored by addition of Ca2+. In contrast, GABA potentiation of noradrenaline-induced [3H]IP accumulation in the same tissue was still observed in the absence of added Ca2+. This provides evidence (a) that the effect of GABA alone on [3H]IP formation is indirect and (b) that the mechanism of this effect is unlikely to be the same as for the potentiation by GABA of [3H]IP accumulation induced by noradrenaline.

Animals↗
PubMed1999

Effects of myo-inositol ingestion on human brain myo-inositol levels: a proton magnetic resonance spectroscopic imaging study.

BACKGROUND: Cerebrospinal fluid levels of myo-Inositol (m-Ino) are reported to be decreased in patients with affective disorder, and dietary supplements of m-Ino have been shown to reduce the symptoms of major depression. Myo-Inositol transport across the blood-brain barrier is mediated by a low capacity, saturable system. This study tests whether dietary m-Ino increases brain m-Ino or changes brain metabolism of m-Ino, possibly explaining the ability of this compound to alter mood. METHODS: Using proton magnetic resonance spectroscopic imaging, we measured m-Ino levels in occipital gray and parietal white matter of seventeen healthy subjects. Magnetic resonance spectroscopic imaging was performed twice at baseline as well as at day 4 and day 8 while subjects ingested 6 g of m-Ino twice a day. RESULTS: Following 4 days of m-Ino, m-Ino/Cr was 20% higher than baseline levels in occipital gray matter (p < 0.04) and 8% higher in parietal white matter (p = ns). By day 8, m-Ino/Cr ratios had returned to baseline values. CONCLUSIONS: Brain m-Ino levels initially increase during m-Ino administration and subsequently return to baseline levels. The time-limited increases observed for brain m-Ino may reflect homeostatic mechanisms, possibly associated with the role of m-Ino as a cerebral osmolyte, or with changes in brain phosphoinositide metabolism.

Adult↗
PubMed1998

Diphospho-myo-inositol phosphates in Dictyostelium and Polysphondylium: identification of a new bisdiphospho-myo-inositol tetrakisphosphate.

The two major diphospho inositol phosphates from the axenic strain Dictyostelium discoideum AX2 were previously investigated and identified as 6-PP-InsP5 and 5,6-bis-PP-InsP4. In order to examine whether these findings are representative of Dictyostelids in general, five non-axenic wild-type species of Dictyostelium and two of Polysphondylium were studied. It was found that all of the Dictyostelium species exhibit similar patterns of diphospho inositol phosphates. By contrast, both of the Polysphondylium species contain 5-PP-InsP5 as the predominant isomer. Besides 5,6-bis-PP-InsP4, a new bis-PP-InsP4 was detected in Polysphondylium. This compound is either 1,5-bis-PP-InsP4 or its corresponding enantiomer 3,5-bis-PP-InsP5. The structures were elucidated by two-dimensional 1H-1H and 1H-31P NMR analysis. Additionally, they were confirmed using a specific 6-PP-InsP(5)-5-kinase from D. discoideum AX2 as an enantio-specific tool and enantiomerically pure reference standards.

Animals↗
PubMed2001

High-performance liquid chromatographic analysis for a non-chromophore-containing phosphatidyl inositol analog, 1-((1-O-octadecyl-2-O-methyl-sn-glycero)phospho)-1D-3-deoxy-myo-inositol, using indirect UV detection.

Phosphatidylinositide-3-kinase (PI3 kinase) is an important constituent of growth factor regulation. It is also involved in oncogene signaling pathways. An ether-containing phosphatidyl inositol(PI) analog, OMDPI, 1-[(1-O-octadecyl-2-O-methyl-sn-glycero)-phospho]-1D-3-deoxy-myo-inositol, is a potent inhibitor of this pathway and may be clinically useful in the treatment of a variety of neoplasms. OMDPI is currently being investigated as an anti-tumor agent by the National Cancer Institute, NIH. OMDPI, a non-chromophore-containing PI analog, is not directly adaptable to the commonly used UV detection of HPLC. This paper reports the development and validation of an HPLC assay for OMDPI based on indirect UV detection, in which a UV-absorbing ion-pair reagent (the probe), protriptyline, is added to the mobile phase to induce a signal for the compound. The method is sensitive (limit of detection <5 microl of 1 microg/ml or 5 ng), precise (R.S.D.<2.5%), linear (r2=0.9995) and accurate (error<0.7%). It is superior to refractive index detection and evaporative light scattering detection in either sensitivity or linearity and does not require special equipment.

Chromatography, High Pressure Liquid↗
PubMed2002

Effects of exogenous inositol hexakisphosphate (InsP(6)) on the levels of InsP(6) and of inositol trisphosphate (InsP(3)) in malignant cells, tissues and biological fluids.

InsP(6) is abundant in cereals and legumes. InsP(6) and lower inositol phosphates, in particular InsP(3), participate in important intracellular processes. In addition, InsP(6) possess significant health benefits, such as anti-cancer effect, kidney stones prevention, lowering serum cholesterol. Because of the insensitivity of existing methods for determination of non-radiolabeled inositol phosphates, little is known about the natural occurrence, much less on the concentrations of InsP(6) and InsP(3) in biological samples. Using gas chromatography-mass detection analysis of HPLC chromatographic fractions, we report a measurement of unlabeled total InsP(3) and InsP(6) (a) as they occur within cells culture, tissues, and plasma, and (b) their changes depending on the presence of exogenous InsP(6). When rats were fed on a purified diet in which InsP(6) was undetectable (AIN-76A) the levels of InsP(6) in brain were 3.35 +/- 0.57 (SE) micromol.kg(-1) and in plasma 0.023 +/- 0.008 (SE) micromol.l(-1). The presence of InsP(6) in diet dramatically influenced its levels in brain and in plasma. When rats were given an InsP(6)-sufficient diet (AIN-76A + 1% InsP(6)), the levels of InsP(6) were about 100-fold higher in brain tissues (36.8 +/- 1.8 (SE)) than in plasma (0.29 +/- 0.02 (SE)); InsP(6) concentrations were 8.5-fold higher than total InsP(3) concentrations in either plasma (0.033 +/- 0.012 (SE)) and brain (4.21 +/- 0.55 (SE)). When animals were given an InsP(6)-poor diet (AIN-76A only), there was a 90% decrease in InsP(6) content in both brain tissue and plasma (p < 0.001); however, there was no change in the level of total InsP(3). In non-stimulated malignant cells (MDA-MB 231 and K562) the InsP(6) contents were 16.2 +/- 9.1 (SE) micromol.kg(-1) for MDA-MB 231 cells and 15.6 +/- 2.7 (SE) for K 562 cells. These values were around 3-fold higher than those of InsP(3) (4.8 +/- 0.5 micromol.kg(-1) and 6.9 +/- 0.1 (SE) for MDA-MB 231 and K562 cells respectively). Treatment of malignant cells with InsP(6) resulted in a 2-fold increase in the intracellular concentrations of total InsP(3) (9.5 +/- 1.3 (SE) and 10.8 +/- 1.0 (SE) micromol.kg(-1) for MDA-MB 231 and K562 cells respectively, p < 0.05), without changes in InsP(6) levels. These results indicate that exogenous InsP(6) directly affects its physiological levels in plasma and brain of normal rats without changes on the total InsP(3) levels. Although a similar fluctuation of InsP(6) concentration was not seen in human malignant cell lines following InsP(6) treatment, an increased intracellular levels of total InsP(3) was clearly observed.

Animal Feed↗