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PubMedDate not supplied

Polyol pathway and NADPH-dependent reductases in dog leukocytes.

Recent reports suggest that excess amounts of sugar alcohol are linked to leukocyte dysfunctions associated with diabetes. As the polyol pathway has not been firmly established in leukocytes, we have investigated NADPH-dependent reductases and sugar alcohol formation in dog leukocytes. NADPH-dependent reductase activity was observed with DL-glyceraldehyde as substrate in both mononuclear and polymorphonuclear leukocytes isolated from dog. By chromatofocusing, this activity corresponded primarily to aldehyde reductase rather than aldose reductase. The enzymatic conversion of glucose to the sugar alcohol sorbitol in leukocytes was confirmed in vitro by 19F nuclear magnetic resonance (NMR) spectroscopy using 3-deoxy-3-fluoro-D-glucose as substrate. The NMR spectrum obtained after incubation with 10 Mm 3-deoxy-3-fluoro-D-glucose at 37 degrees C for 24 h displayed newly formed 3-deoxy-3-fluoro-D-sorbitol and 3-deoxy-3-fluoro-D-fructose peaks with both mononuclear and polymorphonuclear leukocytes. Sugar alcohol production in leukocytes from galactose-fed dogs was also observed in vivo. Galactitol accumulation was consistently observed by gas chromatography to occur in mononuclear cells while only trace amounts of galactitol were observed in polymorphonuclear leukocytes. Activation of NADPH oxidase activity in neutrophils isolated from galactose-fed dogs by zymosan was also significantly reduced compared to that of nongalactosemic control dogs. These results indicate that glucose is converted to fructose through sorbitol in both mononuclear and polymorphonuclear leukocytes despite the observations that these cells primarily contain aldehyde reductase rather than aldose reductase. In vivo, sugar alcohol accumulation in mononuclear cells is greater than in polymorphonuclear leukocytes.

Aldehyde Reductase↗
PubMed2005

[Congenital galactosaemia: an unusual presentation].

Congenital galactosaemia reveals usually in the second and third weeks of life with a severe liver dysfunction. We report on a case of congenital galactosaemia with, on the one hand, an early onset liver failure, without any free interval, and on the other hand, an hemophagocytic syndrome as a severe secondary outbreak with pulmonary haemorrhage. Appropriate diet led to normalisation of liver function. Hemophagocytosis, probably linked to an associated Klebsiella Pneumoniae sepsis, had a favourable outcome after antibiotic and corticosteroid therapy.

Galactosemias↗
PubMed2005

The effect of diet on total antioxidant status, erythrocyte membrane Na+,K+-ATPase and Mg2+-ATPase activities in patients with classical galactosaemia.

OBJECTIVE: Classical galactosaemia is characterized by high levels of galactose-1-phosphate (Gal-1-P), galactose and galactitol. In vitro studies have shown modulation of the rat brain Na+,K+-ATPase and Mg2+-ATPase activities by Gal-1-P. The aim of this study was to evaluate the erythrocyte membrane Na+,K+-ATPase and Mg2+-ATPase activities in galactosaemic patients and to correlate them to Gal-1-P, total antioxidant status (TAS) and membrane protein content (PC). PATIENTS AND METHODS: Nine patients (N=9) originally on "loose diet" (group B) were requested to follow their diet strictly (group A). Twelve healthy children were the controls (group C). The activities of the enzymes, TAS and Gal-1-P in blood were determined spectrophotometrically. In the in vitro study, erythrocyte membranes from controls were preincubated with Gal-1-P (300 microM), and then with l-cysteine (0.83 mM) or reduced glutathione (0.83 mM) whereas these from the patients with the antioxidants only. RESULTS: Na+,K+-ATPase, Mg2+-ATPase, TAS and PC were significantly (P<0.001) reduced (0.31+/-0.03, 1.7+/-0.2 micromol Pi/hxmg protein, 0.89+/-0.02 mmol/l, 36.8+/-2.0 g/l, respectively) in group B as compared with those of group A (0.58+/-0.06, 2.5+/-0.2 micromol Pi/hxmg protein, 1.41+/-0.11 mmol/l, 51.5+/-3.1g/l, respectively) and controls (0.67+/-0.05, 3.2+/-0.2 micromol Pi/hxmg protein, 1.65+/-0.12 mmol/l, 64.0+/-3.5 g/l, respectively). Gal-1-P levels in group B was significantly higher than those in group A and controls. Positive correlation coefficients were found between the enzyme activities, PC and TAS whereas Gal-1-P inversely correlated to the enzyme activities. Incubation of the erythrocyte membranes from the patients with the antioxidants failed to restore the activities of inhibited enzymes, whereas the inhibition by Gal-1-P in controls was reversed. CONCLUSIONS: High blood Gal-1-P concentrations resulted in low TAS and PC. The inhibition of Na+,K+-ATPase and Mg2+-ATPase may be due to the presence of free radicals and/or the elevated Gal-1-P.

Antioxidants↗
PubMed2006

Aqueous flow in galactose-fed dogs.

Dogs fed galactose develop diabetes-like ocular complications that include keratopathy, cataracts, and retinopathy. The purpose of this study was to investigate whether galactosemic dogs display reduced aqueous flow similar to that observed in patients with insulin-dependent diabetes mellitus. Twelve male beagles at 9 months of age were divided into three groups of four. The Galactose group was fed diet containing 30% galactose for 97 months and the Reversal group was fed the galactose diet for an initial 38 months then standard dog diet for the remaining period. The Control group was fed standard dog diet for 97 months. Aqueous flow was determined by fluorophotometry in one eye per dog at 96 and 97 months after the initiation of galactose feeding. Intraocular pressure (IOP) was measured once in the morning by pneumatonometry. Anterior chamber depth was measured by A-scan. At the end of the experiment, eyes were enucleated and processed for histological examination. Dogs fed galactose diet for 97 months had significantly (p<0.05) increased body weights but similar IOP and anterior chamber depth compared to the other groups, and significantly (p=0.05) reduced aqueous flow compared to the control group (4.4+/-2.2 vs. 6.8+/-2.4 microl/min, mean+/-standard deviation, respectively). Additionally, aqueous flow decreased in the Reversal group to 3.1+/-1.3 microl/min (p=0.002). This decrease correlated with morphological changes of the ciliary processes. Like patients with insulin-dependent diabetes mellitus, galactose-fed dogs demonstrate reduced aqueous flow. This reduction was irreversible and independent of the retinopathy present. This animal model may be useful for the study of aqueous humor dynamics in diabetes.

Animals↗
PubMed2005

Q188R, K285N, and N314D mutation-associated alleles in the galactose-1-phosphate uridyltransferase gene and female infertility.

In a retrospective case-control study, the frequencies of Q188R, K285N, N314D, and IVS5-24G>A mutations were determined with the use of polymerase chain reaction and restriction fragment length polymorphism in the group of infertile women and the controls. No statistically significant differences were observed in the allele frequencies between the infertile women and control groups.

Adult↗
PubMed2004

Galactonate determination in urine by stable isotope dilution gas chromatography-mass spectrometry.

A stable isotope dilution assay was developed for the sensitive determination of D-galactonic acid. D-[U-13C(6)]galactono-1,4-lactone was prepared as internal standard. Unlabelled and U-13C-labelled D-galactonic acid species were converted to the N-(1-butyl)galactonamide pentaacetate derivatives and assessed by gas chromatography-mass spectrometry (GC-MS). Positive chemical ionisation and monitoring of the [MH-60](+)-ions in the galactonate chromatographic peak at m/z 402 and m/z 408 were used for quantification. The procedure was applied to study the variability of D-galactonate excretion in healthy subjects and galactosemic patients and to monitor the D-galactonate-D-galactitol ratio in human urine.

Adolescent↗
PubMed2004

Protective effect of L-cysteine and glutathione on the modulated suckling rat brain Na+, K+, -ATPase and Mg2+ -ATPase activities induced by the in vitro galactosaemia.

UNLABELLED: Galactosaemia is an inborn error of galactose (Gal) metabolism characterized by irreversible brain damage. The aim of this study was to evaluate whether the antioxidants L-cysteine (Cys) and the reduced glutathione (GSH) could reverse the alterations of brain total antioxidant status (TAS) and the modulated activities of the enzymes Na+,K+ -ATPase and Mg2+ -ATPase in in vitro galactosaemia. Mixture A (mix. A: galactose-1-phosphate (Gal-1-P, 2mM) plus galactitol (Galtol, 2mM) plus Gal (4mM) = classical galactosaemia) or Mixture B (mix. B: Galtol (2mM) plus Gal (1mM) = galactokinase deficiency galactosaemia) were preincubated in the presence or absence of Cys (0.83mM) or GSH (0.83 mM) with whole brain homogenates of suckling rats at 37 degrees C for 1h. TAS and the enzyme activities were determined spectrophotometrically. The preincubation of brain homogenates with mix. A or mix. B resulted in a decrease of TAS to 30% (P < 0.01), while the presence of Cys or GSH increased TAS to 20% (P < 0.01) and 60% ( P < 0.001), respectively. The antioxidants reversed the inhibited Na+,K+ -ATPase by mix. A or mix. B and the stimulated Mg2+ -ATPase by mix. B to control values, whereas no effect was observed on the enormously activated Mg2+ -ATPase by mix. A. CONCLUSIONS: (a) Gal and its derivatives may produce free radicals in the suckling rat brain, reported for first time, (b) Na+,K+ -ATPase inhibition and Mg2+ -ATPase activation are probably due to the oxidative stress from the above compounds, (c) Cys or GSH could play a protective role reversing the inhibited Na+,K+ -ATPase toward normal in in vitro galactosaemia and (d) the addition of the above antioxidants may reduce the consequences of brain Mg2+ -ATPase activation by Gal and Galtol in galactokinase deficiency galactosaemia.

Animals↗
PubMed2005

Mg2+-ATPase activity in suckling rat brain regions in galactosaemia in vitro. L-Cysteine and glutathione effects.

UNLABELLED: Mg2+-ATPase activity is implicated with Mg2+ homeostasis, maintaining high brain intracellular Mg2+ content. We determined the in vitro effects of galactose-1-phosphate (Gal-1-P), galactitol (Galtol) and galactose (Gal) {mix A=Gal-1-P(2 mM)+Galtol(2 mM)+Gal(4 mM) concentrations commonly found in patients with classical galactosaemia} or Galtol and Gal {mix B=Galtol(2 mM)+Gal(1 mM) concentrations usually measured in patients with galactokinase deficiency galactosaemia} on Mg2+-ATPase activity in suckling rat brain frontal cortex, hippocampus or hypothalamus homogenates. Gal-1-P significantly (p<0.001) enhanced enzyme activity in all the brain areas measured, whereas Galtol and Gal failed to cause any effect in the same regions. Mix A remarkably (p<0.001) stimulated Mg2+-ATPase in the studied areas. On the contrary, mix B had no effect. The supplementation of antioxidant l-cysteine (Cys) or reduced Glutathione (GSH) in mix A failed to reverse to normal the activated enzyme in frontal cortex and hypothalamus, while they significantly reduced Mg2+-ATPase activation in hippocampus. CONCLUSIONS: (a) Gal-1-P enormously activated Mg2+-ATPase in all the studied brain regions, (b) Mix A, also, excessively activated the enzyme in the same areas, (c) the production of free radicals may be implicated with the enzyme activation and (d) Cys or GSH significantly decreased the activated hippocampal Mg2+-ATPase.

Animals↗
PubMed2004

Age dependence of endogenous galactose formation in Q188R homozygous galactosemic patients.

The age dependence of endogenous galactose formation was investigated in Q188R homozygous galactosemic patients (n=18; 4-38 years) using the primed continuous infusion approach with D-[1-13C]galactose as a substrate. Studies were conducted under postabsorptive conditions (fasting >10h) and good metabolic control. In the patients, the release of galactose from endogenous sources into plasma (R(a)) decreased with age and ranged from 4.6 to 2.0 micromol/kg body weight per h. Galactitol and galactonate release rates paralleled the galactose R(a) but at a lower level. The mean relation of galactose, galactitol, and galactonate release was 10:5:1. Statistically, there was a highly significant (p<0.0001) inverse correlation between total galactose release (i.e., sum of R(a) plus galactitol and galactonate release) and age. The data (total galactose=y, age=t) were best fitted to the simple exponential model y=y(0)+axexp(-bt) by non-linear regression analysis. The parameter estimates were y(0)=3.0+/-0.2, a=6.5+/-0.4, and b=0.11+/-0.02. The value of y(0) provides an estimate of total galactose release in adult patients (i.e., approximately 13 mg/kg body weight per day), summation operator (y(0)+a) provides an estimate for galactosemic newborns (i.e., approximately 41 mg/kg body weight per day). The data show that significant amounts of endogenous galactose are formed in galactosemic patients with release rates being several fold higher in infants than in adults. The present findings can explain the persistently elevated galactose-1-phosphate levels in erythrocytes-and its age dependence-in galactosemic patients even when under strict dietary treatment.

Adolescent↗
PubMed2004

Frequency distribution of the Los Angeles and Duarte galactose-1-phosphate uridyltransferase variant alleles in the Irish population.

Anonymous population screening was carried out to detect the N314D, Los Angeles (D1), and Duarte (D2) alleles of the galactose-1-phosphate uridyltransferase gene in Ireland using 743 blood samples, covering the Traveller (n = 243) and non-Traveller (n = 500) population groups. The frequency of the N314D substitution was found to be 0.099 overall. D1 allele frequencies were found to be 0.031 and 0.023 in the Traveller and non-Traveller groups, respectively, while D2 allele frequencies were 0.058 and 0.076, respectively. No significant differences in allele frequency were detected between the Traveller and non-Traveller groups, or between the Irish population groups and the literature values for Northern and Western Europe.

Alleles↗
PubMed2004

Galactitol and galactonate in red blood cells of children with the Duarte/galactosemia genotype.

We measured galactitol, galactonate, and galactose-1-phosphate in the red blood cell (RBC) to elucidate the biochemical phenotype of infants with a Duarte/galactosemia (D/G) genotype by isotope dilution GC/MS. The RBC galactonate, galactitol and Gal-1-P were quantified in 14 D/G newborns on a lactose containing formula or breast milk, eight D/G newborns on a galactose-free formula, and 18 D/G children between 1 and 2 years of age that were on a regular diet. The results were compared with those of non-galactosemic subjects of comparable age. In the D/G newborns on regular formula/breast milk, the levels of RBC galactitol, galactonate, and Gal-1-P were significantly higher than those of D/G newborns on diet treatment and non-galactosemic newborns. There was no difference in the levels of RBC galactitol, galactonate, and Gal-1-P between D/G newborns on a lactose-restricted diet and the control group. There appears to be two different responses to dietary galactose intake in D/G children. The first group of D/G children placed on a regular diet after a year of lactose restriction had higher RBC galactitol, galactonate levels than those of non-galactosemic children. The mean level of RBC galactonate was higher and the mean value of RBC galactitol was as high as that of galactosemic (G/G) patients on diet treatment. The second group of D/G children on a regular diet had normal levels of RBC galactitol and galactonate. The levels of RBC Gal-1-P were normal in both groups of D/G patients. The alternative pathway products may reflect galactose intake better than RBC Gal-1-P in D/G children.

Erythrocytes↗
PubMed2005

UDP-galactose pyrophosphorylase in mice with galactose-1-phosphate uridyltransferase deficiency.

UDP-glucose pyrophosphorylase (E.C. 2.7.7.9), encoded by ugp, provides UDP-glucose which is critical to the synthesis of glycogen, and also catalyzes the reaction between UTP and galactose-1-phosphate, yielding UDP-galactose. This activity of UDP-gal pyrophosphorylase (UDP-galPP) suggests a role in an alternate pathway for galactose metabolism in patients with deficiency of galactose-1-phosphate uridyltransferase (GALT). We examined the effects of GALT deficiency and dietary galactose on UDP-glucose pyrophosphorylase (UDP-gluPP) and UDP-galactose pyrophosphorylase activity and ugp expression in liver of mice with homozygous deletion of the critical regions of galt. Activity with glucose-1-phosphate as substrate was significantly higher than that with galactose-1-phosphate. In liver from mice with GALT deficiency (G/G), UDP-galPP activity appeared to be lower than that measured in liver from control (N/N) animals. This difference disappeared when the N/N tissue homogenate was dialyzed to remove residual UDP-glucose, confirming that careful elimination of residual GALT activity is necessary, since GALT has 1000-fold greater activity toward galactose-1-phosphate than that of UDP-galPP in liver homogenates. Prior exposure to conventional mouse chow, high galactose chow, and high glucose chow did not alter UDP-glu PP or UDP-galPP activity. Steady state UGP mRNA levels were determined in tissues from normal and G/G animals. UGP expression was highest in liver, and did not differ by genotype or exposure to high galactose chow. UDP-galPP activity may account for unexplained ability to oxidize galactose in animals with no GALT activity, but is insufficient to alter accumulation of galactose metabolites.

Animals↗
PubMed2005

Pathways of galactose metabolism by galactosemics: evidence for galactose conversion to hepatic UDPglucose.

To determine if classic galactosemics have residual galactose-1-phosphate uridyltransferase (GALT) activity to explain their considerable ability to oxidize galactose over 24 h, we devised a method for assessing their ability to form hepatic UDPglucose (UDPglu), an intermediate in the normal Leloir pathway of galactose metabolism. The protocol involved the single oral administration of 7 mg/kg [2-13C]galactose concomitant with multiple small doses of acetaminophen with measurement of the extent of labeling of urinary acetaminophen glucuronide, the glucuronide moiety being formed from hepatic UDPglu. We performed the study lasting 24 h in two normal subjects and three classic galactosemics, two homozygous for the Q188R mutation and one compound for the Q188R/K258N mutation. The labeling and total excretion of acetaminophen glucuronide was measured in urine by nuclear magnetic resonance techniques. Concomitant with determination of label in the glucuronide measurement was made of galactose oxidation to 13CO2 and the 13C enrichment of plasma glucose. All of the galactosemic patients formed 13C enriched acetaminophen glucuronide indicating that they had converted the labeled galactose to [13C]UDPglu and that residual GALT or another pathway that forms UDPglu is present in hepatic tissue. Compared to the normal whose glucuronide labeling was rapid and short-lived that of the galactosemics was delayed and extended for a long period over 10 h. The extent of isotopic enrichment of glucuronide by galactosemics was comparable to the normals, resulting in a much greater conversion of galactose to UDPglu by the galactosemics. The labeling of the UDPglu pool was reflected by the rate of 13CO2 formation being rapid in the normal with peak labeling at 2-3 h with total oxidation of over 70% in 24 h. The oxidation of the galactosemics was slow with a broad peak of 13CO2 at 10 h and a total excretion of 25-39% of the [13C]galactose administered. The normal subjects formed highly enriched plasma glucose within 30 min while no enrichment of plasma glucose was detected until after 300 min in galactosemics. The exact pathway(s) of galactose metabolism by galactosemics to UDPglu remain to be determined. Their delineation may contribute to new approaches to therapeutic strategies for this enigmatic disorder.

Acetaminophen↗
PubMed2006

Metabolic fate of administered [13C]galactose in tissues of galactose-1-phosphate uridyl transferase deficient mice determined by nuclear magnetic resonance.

The pattern of distribution of galactose and its metabolites was determined in tissues of mice deficient in galactose-1-phosphate uridyl transferase (G/G) 4 h after the administration of 1mg/g of [13C]galactose. Labeled galactose was found in all the tissues examined, the highest amounts in liver and kidney. Each of the tissues had its own pattern of labeling of galactose-1-phosphate (gal-1-P), galactitol and galactonate. [13C]gal-1-P and galactonate concentration was highest in liver while [13C]galactitol was higher in kidney and heart than in other tissues. Muscle had the lowest amounts of these compounds. In contrast, no galactose was found in tissues of normal mice (N/N) except for a minute amount in muscle. No [13C]gal-1-P was found in liver, kidney or brain and only minute amounts in heart and muscle of N/N animals. Barely detectible, labeled galactitol was observed in these tissues except liver, where none was found. [13C]Galactonate was formed in liver comparable to G/G mice. Almost all of the accumulating 13C isotope was found in liver and kidney glucose and lactate in the normal animals. [13C]Glucose and lactate was also found in liver of the G/G animals, but to a lesser extent than in normals, indicating the presence of a pathway in G/G animals for circumventing the block at GALT for the normal conversion of galactose to glucose.

Animals↗
PubMed1982

Elevated hemoglobin A1 in streptozotocin diabetic rats and in rats on sucrose and galactose-enriched diets.

Increased hemoglobin A1 (HbA1) occurs in diabetes mellitus as a direct consequence of hyperglycemia, which causes postsynthetic modification of hemoglobin proportional to blood glucose concentration. Glycosylation of hemoglobin is demonstrable also in vitro, not only by glucose, but with other reducing sugars such as galactose. The purpose of this study was to show that increased HbA1 could be induced by feeding rats a diet enriched either by galactose or sucrose. A third experimental group consisted of rats made diabetic by injection of streptozotocin. Exposure to a diet of 40% galactose resulted in a diabetes-like state with polyuria, weight loss, muscle atrophy, fat depletion, bilateral cataracts, peripheral neuropathy and significantly elevated HbA1. Blood glucose levels were not elevated and after four months of galactose feeding there was hypoglycemia. Total HbA1 was determined by a microcolumn chromatographic procedure, recently made available for clinical use. Increased HbA1 was also found in rats which received a diet of 68% sucrose for several months. The highest values of HbA1 were determined in streptozotocin diabetic rats and there was significant correlation with plasma glucose concentration. Development of experimental models for increased HbA1 by dietary exposure makes it possible to relate increases in HbA1 to measured amounts of sugar included in the diet. Increased HbA1 in galactosemic and diabetic rats provides a biochemical marker which may be correlated with the evolving morphologic changes such as basement membrane thickening occurring in certain tissues in diabetes mellitus.

Animals↗