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At least 19 recordsLinked to original sources

PubMed1991

Hypoxanthine-maintained two-cell block in mouse embryos: dependence on glucose and effect of hypoxanthine phosphoribosyltransferase inhibitors.

The culture conditions under which hypoxanthine maintains a two-cell block in preimplantation mouse embryos were assessed. Hypoxanthine prevented embryo development past the two-cell stage at concentrations as low as 30 nM, and this inhibitory activity required the presence of D-glucose. The action of hypoxanthine plus D-glucose was reversed by glutamine and higher lactate. D-mannose substituted for D-glucose in supporting the inhibitory action of hypoxanthine, but L-glucose, D-fructose, and 2-deoxyglucose were much less effective. Other purine derivatives such as inosine and adenosine, but not xanthosine or uric acid, also blocked development at the two-cell stage at a concentration of 30 microM, and guanosine was inhibitory at higher doses. Assays of hypoxanthine phosphoribosyltransferase (HPRT) activity in lysates of four-cell embryos determined that the drugs 6-mercapto-9-(tetrahydro-2-furyl)-purine (MPTF) and 6-mercaptopurine (6-MP), but not 6-azauridine (6-AzaU), prevented salvage of hypoxanthine. In addition, MPTF and 6-MP produced a significant two-cell block, which did not depend upon the presence of hypoxanthine or D-glucose; whereas 6-AzaU was without effect. When embryos were cultured 2 days in the presence or absence of D-glucose, hypoxanthine salvage was significantly reduced in lysates of four-cell embryos exposed to D-glucose. D-glucose had no effect when added directly to the assay mixture. These data demonstrate that the ability of hypoxanthine to block embryo development at the two-cell stage depends on the presence of D-glucose or other glycolyzable sugars and suggest that inhibition of the purine salvage pathway promotes the two-cell block.

Animals↗

PubMed1983

Hypoxanthine and xanthine levels determined by high-performance liquid chromatography in plasma, erythrocyte, and urine samples from healthy subjects: the problem of hypoxanthine level evolution as a function of time.

The levels of hypoxanthine and xanthine are determined in plasma, erythrocyte, and urine samples by a reverse-phase high-performance liquid chromatographic (HPLC) method. The hypoxanthine concentration increases in erythrocyte and plasma samples when whole blood is stored at room temperature between sampling and centrifugation. Furthermore, the hypoxanthine concentration increases in erythrocyte samples when they are kept apart at room temperature before analysis, whereas the plasma hypoxanthine level remains constant. This result proves an endogenous formation of hypoxanthine in erythrocytes with time, at room temperature. These studies show the necessity of rigorous conditions for the collection, transport, and treatment of blood samples. In order to achieve accurate results, the blood must be centrifuged immediately after collection. The erythrocyte and plasma samples must be stored frozen until deproteinization and HPLC analysis. Under these conditions, the concentrations of hypoxanthine and xanthine in plasma are 2.5 +/- 1 and 1.4 +/- 0.7 microM, respectively. In erythrocyte samples, hypoxanthine concentration reaches 8.0 +/- 6.2 microM.

Chromatography, High Pressure Liquid↗

PubMed1985

Inhibition of utilization of hypoxanthine and guanine in cells treated with the carbocyclic analog of adenosine. Phosphates of carbocyclic nucleoside analogs as inhibitors of hypoxanthine (guanine) phosphoribosyltransferase.

In cell cultures treated with the carbocyclic analog of adenosine (C-Ado, (+/-)-aristeromycin), the utilization of hypoxanthine and guanine has been observed to be blocked. In an attempt to define the mechanism of this inhibition, we have reexamined the metabolism of C-Ado and its effects on the metabolism of guanine and hypoxanthine. In cultures of L1210 cells, C-Ado at a concentration of 25 microM inhibited the utilization of hypoxanthine and guanine for nucleotide synthesis by more than 90% but produced little or no inhibition of the utilization of these bases in cultures of L1210/MeMPR cells which lack adenosine kinase and cannot phosphorylate C-Ado. In cultures of mammalian cells (L1210, HEp-2, and colon-26 cells), C-Ado was converted to the triphosphate (as previously observed) and also to the triphosphate of the carbocyclic analog of guanosine. The presence of coformycin in the medium at a concentration sufficient to inhibit AMP deaminase almost completely prevented the formation of carbocyclic GTP; thus, the deamination of C-Ado monophosphate is essential for the formation of phosphates of carbocyclic guanosine. Since hypoxanthine (guanine) phosphoribosyltransferase is known to be subject to end product inhibition, it was considered likely that phosphates of carbocyclic guanosine or carbocyclic inosine, present in C-Ado-treated cells, were responsible for inhibition of utilization of hypoxanthine and guanine. The 5'-phosphates of the carbocyclic analogs of inosine and guanosine were synthesized and found to be effective inhibitors of the phosphoribosyltransferase. Carbocyclic GMP was a better inhibitor than carbocyclic IMP and was also superior to GMP and IMP; the concentration of C-GMP that produced a 50% inhibition of GMP formation was approximately 1 microM. It is probable that the presence of phosphates of carbocyclic guanosine accounts for the inhibition of utilization of hypoxanthine and guanine in C-Ado-treated cells.

Adenosine↗

PubMed2006

Partial hypoxanthine-guanine phosphoribosyl transferase deficiency without elevated urinary hypoxanthine excretion.

Partial hypoxanthine-guanine phosphoribosyl transferase (HGPRT) deficiency, also known as the Kelley-Seegmiller syndrome, can give rise to a wide range of neurological symptoms, and renal insufficiency. Biochemically, it is characterized by high uric acid concentrations in blood, high uric acid and hypoxanthine excretion in urine, and decreased activity of hypoxanthine-guanine phosphoribosyl transferase activity (HGPRT). However, normal uric acid concentrations in blood and uric acid excretions in urine have been reported. Here, a boy is presented with normal development and suffering from recurrent attacks of acute renal failure with slightly to clearly increased urinary uric acid excretion. Between these attacks, episodes of elevated urinary excretion of uric acid were observed with normal blood concentrations of uric acid and normal urinary excretion of hypoxanthine. HGPRT activity in erythrocytes, leukocytes, and fibroblasts was found to be strongly decreased. This case shows that not only normal blood uric acid but also normal urinary hypoxanthine concentrations do not exclude the diagnosis of partial HGPRT deficiency.

Acute Kidney Injury↗

PubMed1980

Synthesis of potential inhibitors of hypoxanthine-guaine phosphoribosyltransferase for testing as antiprotozoal agents. 2. 1-Substituted hypoxanthines.

Evidence incicating that effective in vivo inhibition of hypoxanthine-guanine phosphoribosyltransferase (HGPRT, EC 2.4.2.8) should produce antiprotozoal activity without significant toxic effects on mammalian hosts prompted syntheses of 1-substituted hypoxanthines bearing functionalized side chains whose groupings might interact with appropriate groupings of HGPRT to form covalent bonds or strong hydrophobic bonds. 3-(Fluorosulfonyl)benzoyl, 4-(fluorosulfonyl)benzoyl, 4-chlorobenzoyl, and bromacetyl derivatives of two parent amines, 1-(2-aminoethyl)-hypoxanthine and 1-(4-aminobenzyl)hypoxanthine, were synthesized for evaluation in this connection. None of these compounds extended the life span of Plasmodium berghei infected mice or showed significant in vitro inhibition of HGPRT from H.Ep.-2 cells, but 1-[2-(bromoacetamido)ethyl]hypoxanthine displayed in vivo activity against Trypanosoma rhodesiense.

Animals↗

PubMed1998

Adenosine and hypoxanthine transport in horse erythrocytes: evidence for a polymorphism in the transport of hypoxanthine via a sodium-dependent cotransporter.

The inward transport of two purines, adenosine and hypoxanthine, at 37 degrees C by horse erythrocytes was compared. No mediated transport of adenosine was detected in horse erythrocytes, nor was saturable, high-affinity binding of the potent facilitated-diffusion inhibitor nitrobenzylthioinosine demonstrable in horse erythrocyte membranes. In contrast, erythrocytes from most horses possessed a saturable sodium-dependent hypoxanthine transporter (apparent K(m), 100 +/- 28 microM; Vmax, 0.20 +/- 0.08 mmol (l cells)-1 h-1; means +/- S.E.M., n = 5). Guanine inhibited hypoxanthine influx (apparent Ki, 24 +/- 6 microM), but adenine and xanthine had no effect. Unlike human erythrocytes, no sodium-independent hypoxanthine transporter was detected in horse erythrocytes. There are, however, a small number of animals (approximately 15%) whose erythrocytes fail to transport hypoxanthine. This variation appears to be under genetic control, but the precise nature of the control is unknown.

Adenosine↗

PubMed1991

The pathogenesis of the Lesch-Nyhan syndrome: ATP use is positively related to hypoxanthine supply to hypoxanthine guanine phosphoribosyltransferase.

In order to explain features of severe hypoxanthine guanine phosphoribosyltransferase (HPRT) deficiency, the Lesch-Nyhan syndrome, a continuous supply of substrate, hypoxanthine, for the enzyme must be generated. This supply must be increased in association with increased ATP turnover. We have shown that ATP turnover continuously supplies hypoxanthine for recycling by the enzyme HPRT and that this supply increases curvilinearly with increasing ATP turnover. The effects of increasing exercise on ATP turnover were examined using a Latin square experimental design. The outputs of hypoxanthine, xanthine, urate and creatinine were measured. The data were then examined statistically.

Adenosine Triphosphate↗

PubMed1990

Hypoxanthine phosphoribosyltransferase activity in tissues and hypoxanthine concentrations in plasma and CSF of the horse in comparison with other species.

1. Plasma hypoxanthine and xanthine concentrations are very low in the horse and low in rat, mouse and greyhound compared to concentrations in beagles, man, sheep and rabbit. 2. Activities in erythrocytes of the main enzyme metabolizing hypoxanthine, hypoxanthine phosphori-bosyltransferase, show a similar pattern (Tax et al., 1976, Comp. Biochem. Physiol. 54B, 209-212); thus low activities have been found where plasma concentrations were low. 3. Hypoxanthine phosphoribosyltransferase activities in horse tissue other than erythrocytes are similar to those in man and rabbit with high activities in brain; this enzyme may therefore be functionally important in equine brain.

Adenosine Triphosphate↗

PubMed1999

Plasma hypoxanthine levels during crystalloid and blood cardioplegias: warm blood cardioplegia increases hypoxanthine levels with a greater risk of oxidative stress.

BACKGROUND: PATIENTS undergoing cardiopulmonary bypass (CPB) are subjected to severe oxidative stress, and frequently show evidence of acute lung injury post surgery. Associations between acute lung injury, oxidative stress, and aberrant ATP catabolism have been made and prompted us to consider whether the purine metabolites xanthine and hypoxanthine alter significantly during CPB when different types of cardioplegia are used. METHODS EXPERIMENTAL DESIGN: retrospective follow up study on stored plasma samples from patients randomly selected to receive either warm blood, cold blood, or crystalloid cardioplegia. SETTING: adult intensive care unit of post graduate teaching hospital. PATIENTS: thirty-eight patients undergoing aortic valve replacement, with or without artery grafting. Operation was carried out by a single surgeon. INTERVENTIONS: all patients received either a homograft aortic valve or a stentless porcine valve. RESULTS: No significant differences in xanthine levels at any time points during CPB, or between the different cardioplegic groups. Hypoxanthine levels were, however, significantly higher in patients receiving warm blood cardioplegia (74.84+/-16.715 microM, p=0.0151), and was most marked at time point 3 when the aortic cross clamp was released. PATIENTS receiving crystalloid cardioplegia showed higher levels of hypoxanthine (44.56+/-10.16 microM) than those receiving cold blood cardioplegia (21.57+/-7.106 microM). CONCLUSIONS: Considering these data together, it suggests that aberrant ATP catabolism, characteristic of ischaemia/reperfusion, is further disturbed during warm blood cardioplegia leading to a marked increase in plasma hypoxanthine levels. This has the potential to further increase oxidative stress during CPB.

Aged↗

PubMed1975

Hypoxanthine phosphoribosyltransferase and hypoxanthine uptake in human erythrocytes.

A system of hypoxanthine uptake and IMP retention was studied and characterized in human erythrocytes. It follows closely the system already described for rabbit erythrocytes[7]. IMP formation and retention are dependent on the activity of hypoxanthine phosphoribosyl-transferase and on intracellular availability of phosphoribosyl pyrophosphate (P-Rib-PP), which is one of the substrates. In the extrecellular medium, neither P-Rib-PP nor GMP -- a potent inhibitor of the enzyme in vitro -- has any influence on IMP retention. The amount of residual hypoxanthine phosphoribosyltransferase in erythrocyte ghost preparations is directly related to the residual hemoglobin content. Thus the enzyme is characterized as typically soluble and "loosely bound" to membranes. There is a slight difference in the kinetic properties of the ghost-bound and the free soluble enzyme. The possible importance of these results for purine uptake and utilization in human red cells is discussed.

Cell Membrane↗

PubMed1986

Human brain hypoxanthine guanine phosphoribosyltransferase: structural and functional comparison with erythrocyte hypoxanthine guanine phosphoribosyltransferase.

A rapid and simple method, based on GMP Sepharose affinity chromatography, was used for the purification of human brain hypoxanthine guanine phosphoribosyltransferase. A single protein band was detected by polyacrylamide gel electrophoresis of the native purified enzyme. A subunit molecular weight of 25,000 was estimated by SDS gel electrophoresis. The Km values for hypoxanthine and phosphoribosyl pyrophosphate were 50 and 111 microM, respectively. The Ki values for GMP and IMP with phosphoribosyl pyrophosphate were 21 and 37 microM, respectively. The purified enzyme from human brain did not differ significantly from the human erythrocyte one in amino acid composition. The brain and erythrocyte hypoxanthine guanine phosphoribosyltransferases showed complete immunochemical identity on Ouchterlony double diffusion.

Amino Acids↗

PubMed1996

Allopurinol- and Hypoxanthine-Copper(II) Compounds. Spectral and Magnetic Studies of Novel Dinuclear Coordination Compounds with Bridging Hypoxanthine.

The synthesis in aqueous solution and pH = 1.0 of several novel Cu(II) compounds with allopurinol and hypoxanthine as heterocyclic ligands and X = Cl(-), Br(-), NO(3)(-), SO(4)(2-), and ClO(4)(-) as anions, together with their spectral and magnetic characterization, is reported. The studies of the Cu(II) systems with these heterocycles and Cl(-) or Br(-) support their Cu(II)(L)(2)(X)(2) character and their interactions through halogen atoms as bridging ligands, leading to a very weak antiferromagnetic coupling. For the Cu(II) compounds with hypoxanthine and X = NO(3)(-), SO(4)(-), or ClO(4)(-), new examples of the cupric acetate type are obtained, showing in all cases similar strong antiferromagnetic coupling. These three cases are new examples of the scarce Cu(II) dinuclear compounds with bridging hypoxanthine which have been reported up to now.

Journal Article↗

PubMed1997

Hypoxanthine regulation of oocyte maturation in the mouse: insights using hypoxanthine phosphoribosyltransferase-deficient animals.

In this study the effects of hypoxanthine (HX) on meiotic maturation were compared using oocytes from mice possessing a hypoxanthine phosphoribosyltransferase null mutation (HPRT-) and from the corresponding HPRT-competent background strain (HPRT+). Oocyte-cumulus cell complexes and cumulus cell-enclosed oocytes (oocytes cultured while enclosed by cumulus cells) from HPRT+, but not HPRT-, mice took up HX and contained significant levels of HPRT activity. In addition, FSH increased, and HX suppressed, the de novo synthesis of purines in HPRT+ complexes, whereas de novo synthesis was elevated in HPRT complexes and was unaffected by FSH or HX. After 3 h of HX treatment, lower frequencies of germinal vesicle breakdown (GVB) were observed in cumulus cell-enclosed than in denuded HPRT+ oocytes; however, identical frequencies of maturation were observed in denuded and cumulus cell-enclosed HPRT oocytes. This demonstrates a direct inhibitory action of HX on the oocyte that does not depend on salvage, plus an additional action of the cumulus cells that requires HPRT activity. Nevertheless, cumulus cells from HPRT- mice are capable of exerting an additional inhibitory action of dibutyryl cAMP (dbcAMP) on the oocyte. A kinetics analysis of FSH action on HX-arrested cumulus cell-enclosed HPRT+ and HPRT- oocytes revealed, first, that the inhibitory effect of the cumulus cells is transient and, second, that HPRT activity is not required for FSH induction of GVB in HX-arrested oocytes. When dbcAMP- or HX-arrested oocytes were treated with FSH, GVB was blocked to the same extent in HPRT- oocytes with the purine de novo synthesis inhibitor, azaserine, but this drug was less effective in HX-treated HPRT+ oocytes. These results confirm the importance of the de novo pathway in hormone-induced maturation and also support a role for purine salvage as an alternative source of nucleotide in this process.

Animals↗

PubMed1982

Metabolism of dITP in HeLa cell extracts, incorporation into DNA by isolated nuclei and release of hypoxanthine from DNA by a hypoxanthine-DNA glycosylase activity.

dITP may be generated from dATP by a slow, nonenzymatic hydrolysis. While [3H]dITP was degraded rapidly to [3H]deoxyinosine by HeLa cell nuclear extracts, no net degradation of [3H]dITP was observed in the presence of physiological concentrations of ATP, apparently because the extract contained deoxynucleoside diphosphate kinase activity that regenerated [3H]dITP from [3H]dIDP. Isolated HeLa cell nuclei, as well as partially purified DNA polymerase alpha, incorporated [3H]dITP into DNA at 50-60% of the rate of [3H]dGTP incorporation. No rapid release of the incorporated radioactivity was observed. The molecular weight of nascent DNA containing dIMP residues, however, decreased slightly after prolonged incubation in the presence of EDTA, suggesting that a repair process is initiated in dIMP-containing chromatin. Furthermore, release of free [3H]hypoxanthine from [3H]dIMP-containing DNA was detected after incubation with nuclear extracts in the presence of EDTA, suggesting the presence of hypoxanthine-DNA glycosylase activity in HeLa cell nuclei.

Cell Nucleus↗

PubMed1983

Cerebrospinal fluid concentrations of hypoxanthine, xanthine, uridine and inosine: high concentrations of the ATP metabolite, hypoxanthine, after hypoxia.

CSF obtained for clinical purposes from newborn, children and adults has been analysed by high pressure liquid chromatography for hypoxanthine, xanthine, inosine, uridine and urate. Large rises in hypoxanthine and to a lesser extent xanthine occur for about 24 h after hypoxia. High concentrations were associated with later evidence of brain damage or subsequent death. Changes in CSF could be independent of those in plasma. Small or negligible rises were associated with localised and generalised infections including bacterial meningitis, fits, or both. Marked and rapid rises were found after death. These estimations may "predict" the extent of brain damage or brain death.

Adult↗

PubMed1994

Hypoxanthine in vitreous humor and cerebrospinal fluid--a marker of postmortem interval and prolonged (vital) hypoxia? Remarks also on hypoxanthine in SIDS.

Hypoxanthine (Hx) is a degradation product of adenosine. Increased concentrations were reported in cases of hypoxia as well as with prolonged postmortem interval (PMI). Hx is recommended as an indicator of prolonged (cerebral) hypoxia, for example in vitamins of sudden infant death as well as a new biochemical method for estimation of postmortem time. The correlation of vitreous Hx values with the time since death was reported to be even higher than the vitreous potassium (K+) values. The authors' investigations on 92 bodies with known time since death gave a completely opposite result: a much higher correlation between vitreous K+ and time since death than vitreous Hx. The possible discrepancies between these different results will be discussed (disturbing of intra-ocular fluid dynamics by repeated sample-taking in the study of Rognum et al. The results published so far on vitreous Hx values in sudden infant death syndrome (SIDS) cases as an indicator for a prolonged cerebral hypoxia are also not convincing. When vitreous concentrations of newborn infants or infants of age < 6 months are compared to those of older infants or adults the vitreous diameter must be taken into consideration (diffusion gradient; Fick's law of diffusion). The discrepant results on vitreous Hx as a measure of vital hypoxia and PMI will be discussed. The authors' results on Hx determinations on cerebrospinal fluid in comparison to cerebrospinal spinal (CSF) potassium will also be briefly addressed.

Adolescent↗

PubMed2001

Hypoxanthine transport in human tumour cell lines: relationship to the inhibition of hypoxanthine rescue by dipyridamole.

Hypoxanthine (HPX) uptake was investigated in four human tumour cell lines previously characterised as being sensitive (ds: A549 and MCF7) or insensitive (di: COR-L23 and T-47D) to dipyridamole (DP)-induced inhibition of HPX rescue from antipurine antifolate-induced growth inhibition. The aim of the study was to determine the mechanism underlying the differential sensitivity of HPX rescue to DP. The time-course of HPX uptake in the two ds cell lines was different in comparison to the two di cell lines. The initial rate of HPX uptake in the di cell lines was more rapid than in the ds cell lines such that at 60 sec the amount of HPX taken up by the former was 2-6 times higher than that taken up by the later. The K(t) and T(max) for HPX transport in di COR-L23 cells were 870 microM and 4.75 microM/10(6) cells/min and 1390 microM and 1.78 microM/10(6) cells/min in ds A549 cells. HPX transport was not sodium-dependent in these cells. Equilibrative nucleoside transporter 2 (ENT2)-mediated thymidine transport was also higher in di cells. DP inhibited HPX uptake into ds cell lines by > or =48% and by < or =20% in the di cell lines. Competition studies with HPX and thymidine transport via ENT2 indicated an overlap between nucleoside and nucleobase transport transporters in the breast cancer cell lines (MCF7 and T-47D). These studies showed that more rapid and extensive HPX uptake, as well as reduced sensitivity to DP inhibition, is associated with the inability of DP to prevent HPX rescue from antipurine antifolate-induced growth inhibition in certain human tumour cell lines.

Affinity Labels↗

PubMed2005

Development of an amperometric hypoxanthine biosensor for determination of hypoxanthine in fish and meat tissue.

A hypoxanthine (Hx) biosensor based on immobilized xanthine oxidase (XO) as the bio-component was developed and studied for the rapid analysis of fish (sweet water and marine) and goat meat samples. The biosensor was standardized for the determination of Hx in the range of 0.05 to 2 mM. Crosslinking with glutaraldehyde in presence of BSA as a spacer molecule was used for the method of immobilization. One layer of gelatin (10%) was applied over the immobilized enzyme layer to reduce the leaching out of enzyme from the membrane (cellulose acetate) matrix. The optimum pH of the immobilized system was determined to be 8.5 at 25 degrees C instead 7.0-7.2 for free enzyme system. Km and Vmax values were determined for the immobilized system. The developed sensor was applied to determine the amount of Hx present in fish and meat over a period of time. The stability of the enzyme immobilized membrane was also tested over a period of 30 days.

Animals↗