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Biomedical subjects

F Van Hoof

Publications and source records attributed to F Van Hoof.

At least 37 records · Page 2Linked to original sources
PubMed1989

Altered acyl-CoA metabolism in riboflavin deficiency.

We have recently described the effects of riboflavin deficiency on the metabolism of dicarboxylic acids (Draye et al. (1988) Eur. J. Biochem. 178, 183-189). As both mitochondria and peroxisomes are thought to be involved, we have examined the activities of various enzymes in these organelles in the livers of riboflavin-deficient rats. Mitochondrial beta-oxidation of fatty acids was severely depressed due to loss of activity of the three fatty acyl-CoA dehydrogenases, whereas there was an enhancement of peroxisomal beta-oxidation due to an increased activity of the FAD-dependent fatty acyl-CoA oxidase, although the activities of other peroxisomal flavoproteins, D-amino acid oxidase and glycolate oxidase, were lowered. Hepatocyte morphometry revealed an increase in the numbers of peroxisomes, indicating a proliferation induced by the deficiency. The mitochondrial acyl-CoA dehydrogenases involved in branched-chain amino acid metabolism were also severely decreased leading to characteristic organic acidurias. There was some loss of activity of the flavin-dependent sections of the electron transport chain (complexes I and II), but these were probably not sufficient to affect normal function in vivo. The specificity of these effects allows the use of the riboflavin-deficient rat as a model for the study of dicarboxylate metabolism.

Acyl Coenzyme A↗
PubMed1989

Coenzyme specificity of mammalian liver D-glycerate dehydrogenase.

D-Glycerate dehydrogenase (glyoxylate reductase) was partially purified from rat liver by anion- and cation-exchange chromatography. When assayed in the direction of D-glycerate or glycolate formation, the enzyme was inhibited by high (greater than or equal to 0.5 mM), unphysiological concentrations of hydroxypyruvate or glyoxylate much more potently in the presence of NADPH than in the presence of NADH. However, the dehydrogenase displayed a much greater affinity for NADPH (Km less than 1 microM) than for NADH (Km = 48-153 microM). Furthermore, NADP was over 1000-fold more potent than NAD in inhibiting the enzyme competitively with respect to NADH. NADP also inhibited the reaction competitively with respect to NADPH whereas NAD, at concentrations of up to 10 mM had no inhibitory effect. When measured by the formation of hydroxypyruvate from D-glycerate, the enzyme also displayed a much greater affinity for NADP than for NAD. These properties indicate that liver D-glycerate dehydrogenase functions physiologically as an NADPH-specific reductase. In agreement with this conclusion, the addition of hydroxypyruvate or glyoxylate to suspensions of rat hepatocytes stimulated the pentose-phosphate pathway. The coenzyme specificity of D-glycerate dehydrogenase is discussed in relation to the biochemical findings made in D-glyceric aciduria and in primary hyperoxaluria type II (L-glyceric aciduria).

Alcohol Oxidoreductases↗
PubMed1989

Developmental patterns of peroxisomal enzymes in amphibian liver during spontaneous and triiodothyronine-induced metamorphosis.

1. Liver catalase, D-amino acid oxidase, urate oxidase of Alytes obstetricans and Xenopus laevis (anuran amphibians) and fatty acyl-CoA oxidase of Alytes were present at all post-embryonic stages. 2. Catalase and D-amino acid oxidase activities increased during spontaneous metamorphosis of the two species. 3. During triiodothyronine-induced metamorphosis of Alytes larvae, catalase and D-amino acid oxidase activities increased after a latent period. 4. Our results suggest that expression of some hepatic peroxisomal enzymes is modulated by thyroid hormones.

Animals↗
PubMed1989

[Efficacy of treatments in experimental toxoplasmosis].

Experimental study of the intraocular penetration of six drugs with therapeutic effect on toxoplasma. A direct and an indirect method are used. The penetration of six drugs administered sub-conjunctival, retrobulbar and intramuscular in one shot is measured in the anterior chamber, the vitreous and the retina-choroid of a healthy rabbit eye. The best results are obtained for: spiramycin, trimethoprim-sulfamethoxazole and clindamycin. The therapeutic efficiency of four drugs on infected rabbit eyes with toxoplasma are studied using an indirect method: pyrimethamine and especially doxycycline have a positive effect.

Animals↗
PubMed1988

Comparison of the metabolism of dodecanedioic acid in vivo in control, riboflavin-deficient and clofibrate-treated rats.

Intravenous administration of dodecanedioate (or hexadecanedioate) to anaesthetized rats resulted in the urinary excretion of medium-chain dicarboxylic acids (adipic, suberic and sebacic acids). In control animals, the recovery of infused dodecanedioate in the form of urinary medium-chain dicarboxylic acids corresponded to 30% of the infused dose (22 mumol/100 g body mass). This excretion was markedly increased in riboflavin-deficient rats (75% of the infused dose) while it was severely decreased in clofibrate-treated animals (less than 5%). The initial velocity of this process was similar in both control and riboflavin-deficient rats. In control animals, halving the infused dose of dodecanedioate to 11 mumol/100 g body mass resulted in a halving of the initial rate of the urinary appearance of medium-chain dicarboxylates, while doubling the amount of dicarboxylate administered to 44 mumol/100 g body mass did not further modify this velocity, but rather prolonged the duration of the excretion of the resulting products. In riboflavin-deficient and clofibrate-treated rats, the hepatic peroxisomal dicarboxylyl-CoA beta-oxidation activity measured as dicarboxylyl-CoA H2O2-generating oxidase and cyanide-insensitive dicarboxylyl-CoA-dependent NAD+ reduction was increased about threefold and tenfold, respectively. Dicarboxylyl-CoA synthetase activity was normal in the clofibrate-treated rat livers but was increased more than tenfold in the livers from the riboflavin-deficient animals. This work provides evidence that in the rat both mitochondria and peroxisomes are involved in the catabolism of dicarboxylates.

Animals↗
PubMed1988

Effects of riboflavin deficiency and clofibrate treatment on the five acyl-CoA dehydrogenases in rat liver mitochondria.

Rats were maintained on a riboflavin-deficient diet or on a diet containing clofibrate (0.5%, w/w). The activities of the mitochondrial FAD-dependent straight-chain acyl-CoA dehydrogenases (butyryl-CoA, octanoyl-CoA and palmitoyl-CoA) and the branched-chain acyl-CoA dehydrogenases (isovaleryl-CoA and isobutyryl-CoA) involved in the degradation of branched-chain acyl-CoA esters derived from branched-chain amino acids were assayed in liver mitochondrial extracts prepared in the absence and presence of exogenous FAD. These activities were low in livers from riboflavin-deficient rats (11, 28, 16, 6 and less than 2% of controls respectively) when prepared in the absence of exogenous FAD, and were not restored to control values when prepared in 25 microM-FAD (29, 47, 28, 7 and 17%). Clofibrate feeding increased the activities of butyryl-CoA, octanoyl-CoA and palmitoyl-CoA dehydrogenases (by 48, 116 and 98% of controls respectively), but not, by contrast, the activities of isovaleryl-CoA and isobutyryl-CoA dehydrogenases (62 and 102% of controls respectively). The mitochondrial fractions from riboflavin-deficient and from clofibrate-fed rats oxidized palmitoylcarnitine in State 3 at rates of 32 and 163% respectively of those from control rats.

Animals↗
PubMed1988

Prenatal diagnosis of Hunter syndrome using fetal plasma.

The X-linked Hunter syndrome or mucopolysaccharidosis II was diagnosed in a male fetus by demonstrating a severe deficiency of iduronate 2-sulphate sulphatase activity in fetal plasma obtained by umbilical fetal blood sampling at 23 weeks of pregnancy. The diagnosis was confirmed after termination of pregnancy.

Female↗
PubMed1988

Type 3 (chronic) GM1 gangliosidosis presenting as infanto-choreo-athetotic dementia, without epilepsy, in three sisters.

Three sisters (ages 27, 24, and 17 years) presented with slowly progressing dystonic dementia and spastic tetraparesis with infantile onset. CSF, bone marrow, and conjunctival cells showed storage vacuoles. Biochemical analysis revealed increased urinary oligosaccharide excretion and decreased activity of acid beta-D-galactosidase and beta-D-fucosidase in serum, leukocytes, and cultured fibroblasts. The parents' enzyme values were in the heterozygous range. This is the only case in the literature of severe dementia associated with the clinical symptoms of type 3 GM1 gangliosidosis. The clinical heterogeneity of GM1 gangliosidosis and the significance of the combination of beta-D-galactosidase and beta-D-fucosidase defects in this syndrome are discussed.

Adolescent↗
PubMed1987

Peroxisomal oxidation of L-2-hydroxyphytanic acid in rat kidney cortex.

A previously unreported metabolite of mammalian phytanic acid catabolism, 2-oxophytanic acid, was identified by gas chromatography/mass spectrometry analysis. The formation of 2-oxophytanic acid was demonstrated to result from the oxidation of L-2-hydroxyphytanic acid, a reaction catalysed by a rat-kidney-cortex H2O2-generating oxidase. The pH optimum for the L-2-hydroxyphytanate oxidase activity was 8.5 and its apparent Km and Vm were about 0.15 mM and 0.35 mumol min-1 (g tissue)-1, respectively. L-2-Hydroxyisocaproate, a substrate of rat kidney L-alpha-hydroxyacid oxidase type B, inhibited the formation of 2-oxophytanate from L-2-hydroxyphytanic acid. Fractionation studies have indicated that 40% of L-2-hydroxyphytanate oxidase was associated with a particulate fraction and that the activity distribution of the oxidase closely paralleled that of catalase, a well known peroxisomal marker enzyme.

Alcohol Oxidoreductases↗
PubMed1987

Bile acids in peroxisomal disorders.

We examined serum bile acids in patients with different peroxisomal disorders. Patients with Zellweger syndrome (n = 23), infantile form of Refsum disease (n = 6) and neonatal adrenoleukodystrophy (n = 4) consistently had increased levels of bile acid precursors. Patients with X-linked adrenoleukodystrophy, (n = 5) classical Refsum disease (n = 3), hyperpipecolic acidaemia (n = 4) and rhizomelic chondrodysplasia punctata (n = 9) did not have increased bile acid precursor levels. Total serum bile acids (41 micrograms ml-1) and the percentage of bile acid precursors (80%) were highest in typical Zellweger patients who died young. Long-living Zellweger patients, neonatal adrenoleukodystrophy patients and infantile Refsum disease patients had, on average, less cholestasis and a lower percentage of bile acid precursors. We also observed that total serum bile acids and the percentage of bile acid precursors decreased with age in long-living Zellweger patients. Screening for bile acid precursors, combined with very long chain fatty acids analysis is, in our experience, an easy and reliable first-line approach to the detection of peroxisomal disorders.

Adrenoleukodystrophy↗
PubMed1986

Pseudo-Zellweger syndrome: deficiencies in several peroxisomal oxidative activities.

We describe an infant girl with a clinical, chemical, and pathologic syndrome remarkably similar to Zellweger cerebrohepatorenal syndrome but whose liver parenchymal cells contained abundant peroxisomes. Peroxisomal L-alpha hydroxy acid oxidase, catalase, and the plasmalogen synthesizing enzyme dihydroxy acetone phosphate-acyl transferase activities were normal; other peroxisomal enzymatic activities, including fatty acyl-CoA oxidase and D-amino acid oxidase, were reduced by 80% to 85%. Oxidation of bile acids and pipecolic acid was also deficient. Autopsy revealed the presence of neuronal heterotopia, renal cortical cysts, adrenal atrophy, and accumulation of very long chain fatty acids. The clinical and pathologic features of this case of "pseudo-Zellweger syndrome" reflect a deficiency in multiple peroxisomal activities rather than a defect in peroxisomal biogenesis. The deficient enzymatic activities require flavin adenine dinucleotide, and the underlying defect may be in the utilization of this cofactor.

Acyl-CoA Oxidase↗
PubMed1986

Changes in myocardial metabolism during therapy in patients with chronic stable angina: a comparison of long-term dosing with propranolol and nicardipine.

The long-term effects of antianginal therapy on coronary blood flow and myocardial metabolism were studied in 35 patients with chronic stable angina. Arterial and coronary sinus blood samples and coronary blood flow measurements were obtained before and after 1 month of oral administration of propranolol or of the calcium antagonist nicardipine. When the data obtained at a fixed heart rate (10% to 15% above the pretreatment sinus rhythm) were compared, no significant differences were evidenced between the propranolol and the nicardipine groups. Coronary blood flow and myocardial oxygen uptake were unchanged with both drugs. Myocardial lactate uptake increased in 11 patients of the propranolol group (from -2 +/- 42 to 66 +/- 47 mumol/min, p less than .001) and in 11 patients of the nicardipine group (from 0 +/- 36 to 31 +/- 29 mumol/min, p less than .001). In these 22 patients, the increase in lactate uptake was accompanied by reductions in uptake of free fatty acids and by a decrease in the coronary sinus concentration of thromboxane B2 from 131 +/- 87 to 61 +/- 32 pg/ml (p less than .01), whereas the transcardiac release of prostacyclin increased. None of these changes in free fatty acids or in prostanoid handling were observed in the nine patients (five in the propranolol and four in the nicardipine group) in whom lactate uptake was not augmented. During pacing-induced tachycardia, the metabolic effects of the two drugs appeared different. Myocardial lactate uptake decreased more in the patients receiving propranolol than in those receiving nicardipine and the combined productions of alanine and glutamine rose by 3.2 +/- 5.8 mumol/min in the propranolol group while it decreased by 3.1 +/- 8.2 mumol/min in the nicardipine group (p less than .025 propranolol vs nicardipine). In conclusion, long-term antianginal therapy with propranolol or nicardipine improved several markers of myocardial ischemia in approximately two-thirds of the patients. Although the changes observed at low heart rates were similar with the two drugs, the data also suggest that better metabolic protection is provided by the calcium antagonist during pacing-induced tachycardia.

Adult↗
PubMed1986

Multiple peroxisomal enzymatic deficiency disorders. A comparative biochemical and morphologic study of Zellweger cerebrohepatorenal syndrome and neonatal adrenoleukodystrophy.

Biologic, morphologic, and biochemical investigations performed in 2 patients demonstrate multiple peroxisomal deficiencies in the cerebrohepatorenal syndrome of Zellweger (CHRS) and neonatal adrenoleukodystrophy (NALD). Very long chain fatty acids, abnormal bile acids, including bile acid precursors (di- and trihydroxycoprostanoic acids), and C29-dicarboxylic acid accumulated in plasma in both patients. Generalized hyperaminoaciduria was also present. Peroxisomes could not be detected in CHRS liver and kidney; however, in the NALD patient, small and sparse cytoplasmic bodies resembling altered peroxisomes were found in hepatocytes. Hepatocellular and Kupffer cell lysosomes were engorged with ferritin and contained clefts and trilaminar structures believed to represent very long chain fatty acids. Enzymatic deficiencies reflected the peroxisomal defects. Hepatic glycolate oxidase and palmitoyl-CoA oxidase activities were deficient. No particle-bound catalase was found in cultured fibroblasts, and ether glycerolipid (plasmalogen) biosynthesis was markedly reduced. Administration of phenobarbital and clofibrate, an agent that induces peroxisomal proliferation and enzymatic activities, to the NALD patient did not bring about any changes in plasma metabolites, liver peroxisome population, or oxidizing activities.

Acatalasia↗
PubMed1985

The microsomal dicarboxylyl-CoA synthetase.

Dicarboxylic acids are products of the omega-oxidation of monocarboxylic acids. We demonstrate that in rat liver dicarboxylic acids (C5-C16) can be converted into their CoA esters by a dicarboxylyl-CoA synthetase. During this activation ATP, which cannot be replaced by GTP, is converted into AMP and PPi, both acting as feedback inhibitors of the reaction. Thermolabile at 37 degrees C, and optimally active at pH 6.5, dicarboxylyl-CoA synthetase displays the highest activity on dodecanedioic acid (2 micromol/min per g of liver). Cell-fractionation studies indicate that this enzyme belongs to the hepatic microsomal fraction. Investigations about the fate of dicarboxylyl-CoA esters disclosed the existence of an oxidase, which could be measured by monitoring the production of H2O2. In our assay conditions this H2O2 production is dependent on and closely follows the CoA consumption. It appears that the chain-length specificity of the handling of dicarboxylic acids by this catabolic pathway (activation to acyl-CoA and oxidation with H2O2 production) parallels the pattern of the degradation of exogenous dicarboxylic acids in vivo.

Animals↗
PubMed1985

Protection of rats by clofibrate against the hypoglycaemic and toxic effects of hypoglycin and pent-4-enoate. An ultrastructural and biochemical study.

An ultrastructural and biochemical study of the toxic and hypoglycaemic effects of hypoglycin and pent-4-enoate was made on the livers of normal and clofibrate-fed rats. Injection of hypoglycin to rats doubles (from 22% to 44%) the volume fraction of mitochondria and decreases (from 1.05% to 0.26%) the volume fraction of peroxisomes in hepatocytes. The fast-acting toxin pent-4-enoate causes few ultrastructural changes except for the accumulation of lipids. In male adult rats fed with 0.5% clofibrate in their diet for 1-2 months, the volume fraction occupied by peroxisomes and mitochondria in hepatocytes rose to 6.26% and 29.5% respectively. Clofibrate feeding apparently protected the animals against the toxic, hypoglycaemic and hypothermic effects of hypoglycin and of pent-4-enoate, and completely prevented the ultrastructural damage caused by hypoglycin. After hypoglycin administration, hepatic mitochondrial butyryl-CoA dehydrogenase activity was inhibited by more than 90% and, surprisingly, the activity of the peroxisomal enzymes studied was largely preserved. When hypoglycin was given to rats fed on a clofibrate-containing diet, the oxidation of decanoylcarnitine, which was incomplete after hypoglycin treatment alone, remained incomplete with uncoupled mitochondria, but became apparently complete with coupled mitochondria. In the latter condition, there was a slowing of the rate during the last quarter of the pulse of oxygen uptake. Further, butyryl-CoA dehydrogenase activity was much less affected by hypoglycin in clofibrate-fed animals. Pent-4-enoate does not inhibit beta-oxidation in coupled mitochondria from clofibrate-treated rats.

Animals↗