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PubMed2003

Inhibitor of apoptosis proteins and ovarian dysfunction in galactosemic rats.

Galactosemia is a genetic disease with deficiency of galactose-1-uridyltransferase, resulting in the accumulation of galactose or galactose-1-phosphate in the blood and tissues. Rats were fed with normal rat chow and with a high-galactose diet for 4 weeks to give control and galactosemic groups, and their ovarian function was studied. The two groups of rats were injected with pregnant mare's serum gonadotrophin (PMSG) and were killed at different time points after human chorionic gonadotrophin (hCG) injection. The number of oocytes ovulated in the controls was significantly higher than in the galactosemic group. Morphometric studies of the ovaries also showed a higher number of corpora lutea in the controls. Western blot analysis of granulosa cells showed that the overall expressions of Fas and FasL were lower in the control group and their expressions of inhibitor of apoptosis proteins (IAPs) were higher than in the galactosemic group, especially at 8 h post hCG injection. TDT-mediated dUTP-biotin nick end-labeling (TUNEL) and immunohistochemical staining of ovarian sections with Ki-67 and IAPs showed more apoptotic granulosa cells in the galactosemic group and the expressions of IAPs in granulosa cells also confirmed the result of the Western blot. These findings support our hypothesis that ovarian dysfunction in galactosemic rats is due to increased apoptosis in granulosa cells of maturing follicles.

Animals↗
PubMed1988

Analysis of sorbitol, galactitol, and myo-inositol in lens and sciatic nerve by high-performance liquid chromatography.

Accumulation of sorbitol or galactitol and depletion of myo-inositol in hyperglycemic conditions such as diabetes and galactosemia involve the activity of aldose reductase and are implicated in hyperglycemia-induced complications such as cataract and neuropathy. A high-performance liquid chromatographic method has been developed for the measurement of polyols in the lens and sciatic nerve of rats. This method comprises polyol extraction from tissues, lyophilization of extracts, derivatization of polyols by the reaction with phenylisocyanate, and HPLC of derivatives with detection at 240 nm. The time needed for each run is less than 25 min, which allows the testing of a large number of samples per day. Sensitivity is very high: as low as 0.5 nmol each of sorbitol, galactitol, and myo-inositol in lyophilized extracts of tissues can be determined. The present method offers a reliable tool to evaluate the in vivo activities of aldose reductase and its inhibitors.

Animals↗
PubMed1992

Colorimetric determination of galactose and galactose-1-phosphate from dried blood.

A colorimetric microassay for the simultaneous quantitative determination of galactose (Gal) and galactose-1-phosphate (Gal-1-P) in dried blood spots is described. An enzymatic reaction involving alkaline phosphatase (EC 3.1.3.1) and galactose dehydrogenase (EC 1.1.1.48) produces NADH, which is coupled with diaphorase (EC 1.8.1.4) and iodonitrotetrazolium violet (INT). The colourless INT is converted to a formazan of red colour the intensity of which is quantitated either photometrically by a microplate reader or determined visually with sufficient sensitivity for screening purposes. We evaluated the assay on 200,000 blood samples in a newborn screening program, and were able to distinguish between classical and milder forms of galactosemia with ease.

Alkaline Phosphatase↗
PubMed1990

Increases in collagen type IV and laminin in galactose-induced retinal capillary basement membrane thickening--prevention by an aldose reductase inhibitor.

Biochemical alterations in the composition of retinal capillary basement membrane components were investigated in galactosemic rats, an animal model that develops basement membrane lesions comparable to those of diabetic retinopathy. Normotensive Wistar-Kyoto rats fed a 30% galactose diet for 9 months developed significant thickening of retinal capillary basement membranes by comparison with animals fed a control test diet (P less than 0.001), or animals on a diet containing 30% galactose and 250 mg kg-1 of the aldose reductase inhibitor sorbinil (P less than 0.001). A quantitative electron microscopic immunogold technique applied on ultrathin sections of the retinas of these animals showed that the labeling densities of collagen type IV and laminin per unit cross-sectional area (which is presumably proportional to the concentrations of these molecules) were significantly increased in the retinal capillary basement membranes of galactose-fed rats, compared with animals on the control test diet. Increases in these two components of basement membranes were prevented by addition of sorbinil to the diet. However, there was no significant change in the labeling density of heparan sulfate proteoglycan (HSPG) core protein in the basement membranes of galactose-fed rats in comparison to animals on either the control diet or galactose-sorbinil diet. Two types of striated fibrillar materials were frequently found in areas of focal thickening of basement membranes of galactose fed rats only. Thinner fibrils reacted strongly with collagen type III antibody, whereas thicker fibrils reacted weakly with collagen type I antibody. Our results indicate that there is an increase in labeling densities of collagen type IV and laminin in thickened basement membranes of retinal capillaries of galactosemic rats along with the expression of interstitial collagens like collagen type III and an abnormal collagen that weakly cross-reacts with antibody to collagen type I, and these effects of galactosemia on the basement membranes are preventable by an aldose reductase inhibitor.

Aldehyde Reductase↗
PubMed1983

The influence of glucose on serum galactose levels in man.

To investigate the effect of simultaneous glucose and galactose administration on serum galactose levels in man, volunteers were given a standard galactose meal of 0.5 g galactose/kg BW alone and with various body weight related glucose loads and with fructose; lactose was also given to a group of volunteers. Two groups of subjects received the standard galactose meal alone and with a simultaneous intravenous infusion of glucose or insulin. There was a marked individual variation in the serum galactose response to the standard galactose meal, the maximum galactosemia ranged from 0.23 to 4.56 mmole/L. Peroral glucose suppressed the serum galactose response to galactose producing significant reductions in the mean area under the serum galactose response curves. At a glucose intake of 0.15 g/kg by-32 +/- 14.3%, 0.50 g/kg BW -69 +/- 5.93% and at 0.75 g/kg BW -75 +/- 4.93%. Ingestion of glucose with galactose did not increase galactose loss in the urine. Lactose produced similar serum galactose, glucose and insulin responses to those seen after administration of equal quantities of galactose and glucose as monosaccharides. Fructose did not affect serum galactose levels when given with the standard galactose meal. Intravenous glucose produced a significant reduction of 56 +/- 14.1% in the mean area under the galactose response curve [p less than 0.01], whereas intravenous insulin did not affect the serum galactose response to peroral galactose.

Adolescent↗
PubMed1985

The effects of a new aldose reductase inhibitor (tolrestat) in galactosemic and diabetic rats.

Tolrestat(N-[[5-(trifluoromethyl)-6-methoxy-1-naphthalenyl] thioxomethyl]-N-methylglycine; AY-27,773; Alredase) is a potent, structurally novel inhibitor of aldose reductase (AR). In vitro, tolrestat inhibited in dose-dependent fashion the AR from bovine lenses (IC50, 3.5 X 10(-8) mol/L) and the formation of sorbitol in human RBC incubated with glucose (IC50, 3 X 10(-8) mol/L). Upon administration with the diet to rats made galactosemic or diabetic, tolrestat decreased, in a dose-related fashion, the accumulation of galactitol or sorbitol in the sciatic nerve and lens. The effectiveness of tolrestat depended upon the experimental conditions and tended to be higher in less severe galactosemia and after suitable pretreatment, particularly in galactosemic rats, resulting in ID50 of 5 mg/kg/d in the sciatic nerve and 12-15 mg/kg/d in the lens. Tolrestat also decreased, in dose-related manner, the RBC sorbitol levels in normal and in streptozotocin diabetic rats; in the latter, at less than 2 mg/kg/d, the RBC sorbitol was reduced to control levels.

Aldehyde Reductase↗
PubMed1986

Hyperglycemia as a cause of diabetic retinopathy.

Diabetes mellitus is marked by hyperglycemia and a variety of other metabolic disorders. The significance of hyperglycemia in the pathogenesis of diabetic retinopathy has proven difficult to evaluate in patients. Diabetic dogs are known to develop retinal lesions morphologically identical to those typical of diabetes in man, provided hyperglycemia in the animal is allowed to persist at least for many months and usually for 3 to 5 years. The development of retinopathy in this animal model can be inhibited by careful improvement of diabetic (glycemic) control. Comparable retinopathy has recently been found to develop in nondiabetic dogs as a result of experimental galactosemia of several years' duration. Included in this retinopathy and in the retinopathy of diabetic patients and dogs as well are saccular capillary aneurysms, hemorrhages, nonperfused or acellular vessels, varicose vessels, and loss of capillary pericytes. Retinal capillary basement membrane has been measured (to date) in two dogs that had been galactosemic for 5 years, and it was found to be significantly thicker than in normal dogs (P less than 0.01). Many metabolic abnormalities typical of diabetes are absent from galactosemic dogs. Unlike diabetic dogs, the blood levels of glucose, nonesterified fatty acids, branched-chain amino acids, and fibrinogen are not elevated in the galactosemic dogs, and their serum insulin concentration seems normal. Excessive blood hexose itself appears to be an important determinant of retinopathy. One possible mechanism by which excessive blood hexose might produce retinopathy involves the polyol pathway.(ABSTRACT TRUNCATED AT 250 WORDS)

Aldehyde Reductase↗
PubMed1995

Comparison of erythrocyte uridine sugar nucleotide levels in normals, classic galactosemics, and patients with other metabolic disorders.

By limiting galactosylation mechanisms, a cellular deficiency of the uridine sugar nucleotide, UDPgalactose, has been implicated as a cause of the long-term complications seen in patients with classic galactosemia despite dietary treatment. As a result, great interest has been generated in the accurate assessment of UDPgalactose, as well as UDPglucose, from which UDPgalactose may be derived by the function of a ubiquitous, active UDPgalactose-4-epimerase. Since several series of values for the concentration of these compounds in red blood cells (RBCs) of galactosemics have been flawed by the use of methods subsequently shown to be unsuitable, we have quantified erythrocyte UDPgalactose and UDPglucose levels by an accurate high-performance liquid chromatography (HPLC) assay in 116 normals, 76 galactosemics, and 39 patients with other metabolic disorders. These large groups have permitted the evaluation of age, diet, and genotype as influential factors in the steady-state RBC levels of the sugar nucleotides. The data show that age is an important determinant of RBC levels, with children younger than 10 years having higher values than individuals older than 10 years. Mean UDPgalactose levels in galactosemic children younger than 10 years and those older than 10 years were 30% and 18% lower, respectively, than levels in comparable normals. Although the mean differences were highly significant, there was considerable overlap of individual values. There was no difference in UDPglucose levels between galactosemics and normals.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMedDate not supplied

Elevated blood viscosity in alloxan diabetic dogs and experimentally galactosemic dogs.

Blood viscosity was investigated in alloxan-diabetic dogs and in dogs made experimentally hyperglycemic by a galactose-rich diet. The diabetics were prospectively assigned to levels of glycemic control ranging from poor to good. After up to 5 years of study, the blood viscosity of hyperglycemic diabetic animals was significantly greater than normal at both high (100 sec-1) and low (0.1 sec-1) shear rates. Blood viscosity at the low shear rate correlated closely with fibrinogen concentration, (r = 0.75; p less than 0.02) but not with HbA1 concentration (r = 0.14) in the diabetics. Galactosemic animals likewise had elevated blood viscosity at the low shear rate, but the correlation of viscosity with fibrinogen concentration in those animals was not statistically significant (r = 0.42). Plasma viscosity tended to be elevated in both diabetes and galactosemia, but not to a statistically significant degree.

Animals↗
PubMed2004

Substrate specificity and mechanism from the structure of Pyrococcus furiosus galactokinase.

Galactokinase (GalK) catalyses the first step of the Leloir pathway of galactose metabolism, the ATP-dependent phosphorylation of galactose to galactose-1-phosphate. In man, defects in galactose metabolism can result in disorders with severe clinical consequences, and deficiencies in galactokinase have been linked with the development of cataracts within the first few months of life. The crystal structure of GalK from Pyrococcus furiosus in complex with MgADP and galactose has been determined to 2.9 A resolution to provide insights into the substrate specificity and catalytic mechanism of the enzyme. The structure consists of two domains with the active site in a cleft at the domain interface. Inspection of the substrate binding pocket identifies the amino acid residues involved in galactose and nucleotide binding and points to both structural and mechanistic similarities with other enzymes of the GHMP kinase superfamily to which GalK belongs. Comparison of the sequence of the Gal3p inducer protein, which is related to GalK and which forms part of the transcriptional activation of the GAL gene cluster in the yeast Saccharomyces cerevisiae, has led to an understanding of the molecular basis of galactose and nucleotide recognition. Finally, the structure has enabled us to further our understanding on the functional consequences of mutations in human GalK which cause galactosemia.

Adenosine Diphosphate↗
PubMed2004

Alternative pathways of galactose assimilation: could inverse metabolic engineering provide an alternative to galactosemic patients?

The galactose assimilation pathway has been extensively studied as an example of a genetic regulatory switch. Besides the importance of this pathway as a tool in basic biological research, unraveling its structure and regulation is also of major medical importance. Impairment of galactose assimilation is the cause of the genetic metabolic disease known as "galactosemia", while the in vivo activity of the pathway affects the production of glycans. The latter have been connected to tumor metastasis, anti-cancer drug resistance and various cardiovascular diseases. Despite the vast amount of studies, however, galactose assimilation and its interaction with other parts of the metabolic network have not been fully elucidated yet. In yeast and higher eukaryotes, it is still being studied as comprising only the linear Leloir pathway. Recent observations, however, indicate that alternative pathways of galactose assimilation identified in prokaryotes and fungi might also be present in yeast. Such a result is valuable per se, because it could lead to the discovery of these pathways in humans. Even more importantly, these pathways provide alternative phenotypes with known genetic fingerprints that can be used in the context of classical and inverse metabolic engineering to examine and treat the mechanisms of defects of galactose assimilation.

Animals↗
PubMed2003

Galactitol and galactonate in red blood cells of galactosemic patients.

The red blood cell (RBC) concentration of galactitol and galactonate was measured in 27 patients with galactose-1-phosphate uridyltransferase (GALT) deficiency galactosemia and 19 non-galactosemic subjects by a newly devised isotope dilution gas chromatography/mass spectrometry (GC/MS) method. The method utilizing UL[13C]galactitol and UL[13C]galactonate was reproducible with excellent precision and recovery of 99%. The RBC galactitol in galactosemic patients on galactose-restricted diets averaged 5.98+/-1.2 microM (M+/-SD) with a range of 3.54-8.81 microM. The mean in non-galactosemic patients was 0.73+/-0.31 microM with a range of 0.29-1.29 microM. The mean of RBC galactonate in the same galactosemic patients was 4.16+/-1.32 microM (M+/-SD) with a range of 0.68-6.47, while the mean in non-galactosemic subjects was 1.94+/-0.96 (M+/-SD) with a range of 0.69-3.84. In galactosemic RBC the galactitol was higher than galactonate while this was reversed in non-galactosemic cells. RBC galactose-1-phosphate (Gal-1-P) measured at the same time as galactitol and galactonate was 30 times the level of the other two metabolites. There was no relationship between RBC Gal-1-P and galactitol or galactonate. The ability to measure all three galactose metabolites in the same procedure offers the possibility of augmented monitoring of the galactose metabolic status of patients. The measurement of RBC galactitol and galactonate presents a new means of characterizing galactosemic patients and their levels monitored over time may provide new insight in the development of long-term complications observed in afflicted patients.

Adolescent↗
PubMed2005

Intracellular galactose-1-phosphate accumulation leads to environmental stress response in yeast model.

In humans, deficiency of galactose-1-phosphate uridyltransferase (GALT) can lead a metabolic disorder Classic Galactosemia. Although the biochemical abnormalities associated with this disease have been described in detail, few attempts have been made to characterize the pathogenic mechanisms of this disorder at the molecular level. Here we report the use of high-throughput DNA microarray to examine how galactose affects gene expression in isogenic yeast models that are deficient in either galactokinase (GALK) or GALT, two enzymes which are essential for normal galactose metabolism. We confirmed that the growth of our GALT-deficient, but not GALK-deficient yeast strain ceased 4 h after challenge with 0.2% galactose. Such inhibition was not associated with a reduction of ATP content and was reversible after removal of galactose from medium. We compared the gene expression profiles of the GALT-deficient and GALK-deficient cells in the presence/absence of galactose. We revealed that in the absence of galactose challenge, a subset of genes involved in RNA metabolism was expressed at a level 3-fold lower in the GALT-deficient cells. Upon galactose challenge, significantly more genes involved in various aspects of RNA metabolism and almost all ribosomal protein genes were downregulated in the GALT-deficient, but not GALK-deficient cells. Remarkably, genes involved in inositol biosynthesis and turnover were exclusively induced at high level in the galactose-intoxicated GALT-deficient cells. Our data thus suggested that RNA metabolism, ribosome biogenesis, and inositol metabolism were likely targets for galactose-1-phosphate, a toxic intermediate that is uniquely accumulated under GALT-deficiency.

Environment↗
PubMed2002

Neonatal biochemical screening for disease.

BACKGROUND: The practice of screening the neonatal population for certain diseases by biochemical testing of a dried blood spot is an established public health initiative in many countries. The diseases for which screening is done vary from region to region, based on ethnic, financial and political considerations. Criteria have been established to identify diseases suitable for neonatal screening. DISEASES SCREENED: In Western countries, screening for phenylketonuria (PKU) and congenital hypothyroidism (CH) has been introduced throughout. Subsequently, cost-benefit analysis has confirmed the existence of a financial benefit. Other diseases screened for in some regions include galactosemia, aminoacidemias and organic acidemias, cystic fibrosis, congenital adrenal hyperplasia, biotinidase deficiency, hemoglobinopathies, glucose-6-phosphate dehydrogenase deficiency, and Duchenne muscular dystrophy, although in no case has a clear financial benefit been established. CONCLUSIONS: Since the introduction of neonatal screening over 40 years ago, new methods have resulted in an increase in the number of diseases amenable to screening, better automation and greater specificity. Methods currently used include growth of an inhibited bacterial auxotroph (the original phenylalanine (phe) method of Dr. Robert Guthrie), spectrophotometry, fluorometry, immunoassay, and tandem mass spectrometry with electrospray ionization.

Adrenal Hyperplasia, Congenital↗
PubMed2002

Identification of galactitol and galactonate in red blood cells by gas chromatography/mass spectrometry.

BACKGROUND: Because the products of alternate pathways of galactose metabolism, galactitol and galactonate are important in galactosemia, we sought to identify these compounds in red blood cells (RBC). METHODS: RBC extracts were trimethylsilylated (TMS) and analyzed by gas chromatography/mass spectrometry (GC/MS). RESULTS: The presence of both galactitol and galactonate was identified in RBC of 15 galactosemic and 13 normal subjects by their mass spectra and chromatographic comparisons with both unlabeled and 13C labeled standards. The levels in RBC of galactosemics appear to be much higher than those of normal subjects. CONCLUSION: The determination of these compounds in RBC along with galactose-1-phosphate (gal-1-P) in the same procedure provides the potential for their use in better monitoring of diet therapy in galactosemic patients.

Erythrocytes↗
PubMed1986

Microassay for estimation of galactose and galactose-1-phosphate in dried blood specimens.

A fluorometric assay for blood galactose and galactose-1-phosphate has been modified and improved to shorten the analysis time and to increase sensitivity above other published methods. The method may be useful as a quantitative screening or routine clinical test to detect infants suspected of having a defect of galactose metabolism. It can also be used to monitor blood galactose or galactose-1-phosphate levels in children with galactosemia who are on a lactose-free diet.

Alkaline Phosphatase↗
PubMed1988

Glutathione depletion in the lens of galactosemic and diabetic rats.

Depletion of lens glutathione (GSH) occurs quickly and drastically following induction of diabetes or galactosemia in rats as well as in lens culture. The explanation for this dramatic loss of GSH has been investigated by many laboratories but the solution has been elusive. There are several possible causes for the change in the reducing power of the lens under hyperglycemia. (a) The enzyme glutathione reductase which reduces oxidized glutathione to GSH is inhibited. (b) The cofactor NADPH which both the aldose reductase of polyol pathway and glutathione reductase require becomes depleted under hyperglycemia to the point that there is an insufficient amount for glutathione reduction. (c) Membrane permeability is increased, due to osmotic-induced lens hydration. We explored all the above possibilities in the mechanism of GSH depletion and studied the effect of aldose reductase inhibitor (ARI) on osmotic change. We found that under hyperglycemic condition, there was no change in the enzyme glutathione reductase activity. There was an initial drop in NADPH level but there was sufficient remaining for glutathione reductase use. Both NADPH and glutathione depletion could be prevented completely by ARI. In addition, ARI could also prevent any hyperglycemic-induced abnormal transport and leakage of amino acids. We have therefore concluded that only the decreased membrane transport of amino acids which are needed for glutathione biosynthesis and the simultaneous loss of GSH through leaky membrane as initiated by the polyol pathway can be responsible for the drastic GSH depletion.

Aldehyde Reductase↗
PubMed1985

Perinatal galactose metabolism.

Galactose is a major nutrient in normal newborn infants and serves as a substrate for energy production and fuel storage and a regulator of carbohydrate assimilation. Inborn errors of galactose metabolism have contributed to our understanding of the potential toxicity of this carbohydrate. In addition to the classic acute manifestations of neonatal galactosemia, long-term follow-up of surviving patients have revealed unusual neurodevelopmental and reproductive problems. Many investigators have suggested that the newborn infant can utilize galactose better than adults and that neonatal galactose assimilation exceeds that of glucose. Galactose may be an excellent substitute for glucose among hyperinsulinemic infants of diabetic mothers or premature infants with glucose intolerance. However, until further investigations are performed to define the role of galactose in newborn nutrition and to determine its potential toxicity, galactose should not be used as the primary carbohydrate in sick newborn infants.

Cell Membrane Permeability↗