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Biomedical subjects

G Novelli

Publications and source records attributed to G Novelli.

At least 217 records · Page 12Linked to original sources
PubMed1985

In vivo and in vitro inhibition of hepatic microsomal drug metabolism by ketoconazole.

Ketoconazole (KC), a broad spectrum antifungal drug, has been recognized recently as a cause of hepatic injury. The mechanism of the adverse reaction remains unclear: a metabolic idiosincrasy has been suggested. However as a substituted imidazole, KC might be expected to interfere with the hepatic microsomal mixed function oxidases. Ethylmorphine N-demethylase (E-DM) and aniline hydroxylase (A-OH) activities were determined in rat liver microsomes in the presence of increasing amounts of KC. Both were inhibited in an exponential fashion. The E-DM inhibition was almost complete at concentrations greater than 250 microM and was of the mixed type. A much weaker effect was observed for A-OH. A significant inhibition of E-DM was also observed when KC was administered in vivo to rats either orally for 7 days at the dose of 100 mg/kg/day (P less than 0.02) or intraperitoneally for 4 days at the dose of 50 or 100 mg/kg day (P less than 0.01 or P less than 0.001 respectively). A-OH activity was significantly reduced (P less than 0.01) only after ip administration of 100 mg/kg/day of the drug for 4 days. Neither the amount of cytochrome P-450 nor NADPH cytochrome c reductase activity were affected at the doses considered. These data show that KC interferes with hepatic oxidative drug metabolism and suggest that this mechanism might be involved in the unwanted side effects of therapy with KC.

Administration, Oral↗
PubMed1985

Hereditary nonspherocytic hemolytic anemia due to a new hexokinase variant with reduced stability.

A 27-year-old woman with severe chronic hemolytic anemia was found to have reduced red cell hexokinase activity when the degree of reticulocytosis was considered. This enzyme had normal pH-dependent activity, normal Km for glucose, fructose, and mannose, normal Km for Mg adenosine triphosphate (ATP)2- and Ki for glucose-1,6-diphosphate. Furthermore, the pH-dependence and orthophosphate dependence of Ki for glucose-1,6-diphosphate were normal. However, this hexokinase was inactivated rapidly at 44 degrees C. No abnormalities were found in the red cell hexokinase isozymic pattern when it was compared with the profile obtained from cells of similar age. The hexokinase specific activity was reduced in all the red blood cell fractions obtained by density gradient ultracentrifugation; a marked difference in the distribution of cells through the gradient was evident. Among the glycolytic intermediates, a significant decrease of 2,3-diphosphoglycerate was evident. ATP and glucose 6-phosphate were also reduced when compared with cells of similar. Glucose consumption of the hexokinase-deficient cells decreased, but the rate of glucose metabolized through the hexose monophosphate shunt was unchanged. Although the total hexokinase activity in lymphocytes was only reduced by 37%, a marked hexokinase deficiency was detected in blood platelets (20% to 25% of normal activity). The parents and one of two siblings of the patient were heterozygous for the defect, with 66% to 74% of normal erythrocyte hexokinase activity and reduced heat stability of the enzyme. These results, when compared with those obtained in previously reported cases of hexokinase deficiency, provide further evidence of the broad phenotypic variability that characterizes this disorder. Furthermore, it is suggested that failure of energy generation is probably the primary cause of hemolytic anemia in hexokinase deficiency.

Adult↗
PubMed1984

Interstitial deletion of chromosome 1 (q23-q25). Report of a case.

We describe a 3-month-old female with a de novo interstitial deletion of the long arm of chromosome 1 (1q23-25). Clinical features are failure to thrive, psychomotor retardation, cleft lip and palate, short metacarpals, metatarsals and fingers and a severe congenital heart disease. The four previously reported patients with the same deletion share with ours the distinctive pattern of anomalies of the face and limbs; therefore, it seems now possible to delineate a proximal 1 q deletion syndrome.

Abnormalities, Multiple↗
PubMed1984

Changes induced in human liver by long-term anticonvulsant therapy. Functional and ultrastructural data.

The study reports functional and morphological findings in eight male subjects undergoing anticonvulsant therapy for periods from 20 days up to 15 years. All subjects showed an increased activity of the hepatic microsomal NADPH cytochrome c reductase and an increased amount of smooth membranes in hepatocytes. The enzymatic activity was higher in the first years of treatment. Quantitative ultrastructural analysis showed that a twofold increase of the smooth membranes of hepatocytes had already been reached after 20 days of therapy, with a modest additional increase occurring thereafter. Both enzymatic and structural changes appear to be related to therapy. In addition, abnormal lipofuscin-related cytoplasmic formations were present in the hepatocytes of five subjects. Such formations are thought to represent an accumulation of abnormal degradation products, possibly related to an interaction of the drug(s) metabolites with cellular components.

Adult↗
PubMed1984

A live infant with trisomy 14 mosaicism and nuclear abnormalities of the neutrophils.

Mosaic trisomy 14 is described in a patient with severe developmental retardation and congenital malformations. Together with a few previous reports, this case suggests the existence of a syndrome associated with this chromosome imbalance. Hitherto unrecognised manifestations of trisomy 14 mosaicism were, in our patient, abnormalities of the neutrophil nuclei, which consisted of multiple pedunculated or sessile projections, similar to those characteristically associated with trisomy 13 syndrome.

Abnormalities, Multiple↗
PubMed1984

Regional mapping of hexokinase-1 within the short arm of chromosome 10.

Hexokinase-1 (HK1) activity was determined in red cells of 5 patients with partial duplications of chromosome 10, all of which involved the 10p region. In 4 patients the levels of HK1 activity were higher than the mean activity of controls, strongly indicating a triplex dosage effect. The most likely regional assignment for HK1 would appear to be 10p11.2.

Child↗
PubMed1984

Red blood cell hexokinase in Fanconi's anemia.

The activity of ten red blood cell enzymes, including hexokinase, has been measured in 6 Fanconi's anemia patients. In disagreement with previous reports, in no instance were reduced or increased hexokinase levels found. Furthermore, the hexokinase isozymic pattern, thermostability, pH dependence of activity and kinetic properties were also in the normal range.

Adolescent↗
PubMed1984

Human plasma glutathione oxidation in normal and pathological conditions.

Reduced glutathione added to human plasma disappears rapidly, and it is concomitantly recovered in its oxidized form. This oxidation is not due to the plasma metal content since it is not inhibited by EDTA or by passage of plasma through Chelex columns. Furthermore, this oxidation is not due to the peroxidase activity of glutathione S-transferases, which are usually undetectable in normal human serum, and it does not correlate with the amount of plasma glutathione peroxidase. A significant increase in the rate of glutathione oxidation was observed in plasma of patients with increased gamma-glutamyltranspeptidase activity. It is concluded that the side-oxidase activity of gamma-glutamyltransferase is responsible for the oxidation of glutathione in human plasma.

Glutathione↗
PubMed1984

Comparative effects of cimetidine on biliary lipid secretion in fasted and fed rats.

The effect of cimetidine on biliary lipid secretion has been investigated in fasted and fed rats with biliary drainage for 4 h after a single intraperitoneal administration at a dose of 120 mg/kg body weight. Bile flow, bile acids, cholesterol and phospholipids in bile have been determined. In intact rats similarly treated, serum bile acids, cholesterol and phospholipids have been determined. Biochemical and morphological studies have been conducted on the liver tissue in both experiments. Bile flow and bile acid secretion were not affected by cimetidine in fasted rats, but, 15 min after administration of the drug, fed rats showed an increase of the molar percentage of cholic acid together with a decrease of deoxycholic acid, a decreased secretion of cholesterol and an increased secretion of phospholipids. The values of these biliary lipids were in the range observed in fasted animals, so that the drug appeared to 'mimic' the effect of fasting. These findings could be related to altered vascular properties of the gastro-intestinal wall induced by cimetidine, leading to interference with intestinal postprandial hyperaemia and capillary permeability, so that there appears to be a conversion of bile composition from a digestive to an interdigestive pattern.

Animals↗
PubMed1984

Cytochemistry of cell surface sialoglycoconjugates in endometrial adenocarcinoma. Effects of medroxyprogesterone therapy.

Ferritin- and rhodamine-conjugated Limulus polyphemus agglutinin was used to localize, by electron microscopy, and to quantify, by microfluorometry, the cell surface sialoglycoconjugates in human endometrial adenocarcinoma before and after medroxyprogesterone acetate therapy. In the untreated tumor the lectin labelling was irregularly distributed on the cell surface, with a maximum density at the apical area and at the intercellular border; high values of the density-binding sites on cell surface were also detected by cytofluorometry. The binding pattern in both electron microscopy and microfluorometry on normal tissue and on tumor tissue submitted to medroxyprogesterone acetate stimulation appeared clearly modified; the lectin labelling concerned the apical areas only (also after treatment with chelating agents), with low fluorometric values of the reactive site density. The differences found in the lectin binding to the cellular sialic acid residues may be due to sialoglycoconjugate quantitative changes and/or to their different reactivity resulting from alterations of the cell membrane architecture. The data appear also correlated with a different proliferative activity and ploidy level of the three situations analyzed.

Adenocarcinoma↗
PubMed1983

Pig red blood cell hexokinase: evidence for the presence of hexokinase types II and III, and their purification and characterization.

Pig erythrocytes, in contrast to red blood cells from other mammals (M. Magnani, V. Stocchi, F. Canestrari, M. Dachà, and G. Fornaini (1982) Biochem. Int. 4, 673), have been shown to contain hexokinase (EC 2.7.1.1) types II and III. Hexokinase type III is the predominant form, accounts for 98% of the total glucose phosphorylating activity, and has been purified 290,000-fold by a combination of ion-exchange chromatography and affinity chromatography on Sepharose-N-hexanoylglucosamine. The enzyme was shown to be homogeneous by polyacrylamide and sodium dodecyl sulfate-gel electrophoresis. The highest specific activity obtained was 190 units/mg protein with a yield of 60%. Because the amount of hexokinase II was small, it was only partially purified by ion-exchange chromatography. The native proteins have the same molecular weight of 100,000 by gel filtration on Ultrogel AcA44. The apparent isoelectric point of hexokinase type II was shown to be 4.8 and 4.9 pH units, whereas hexokinase type III was shown to have a pI of 4.3 to 4.4 pH units by isoelectric focusing. Both hexokinases are able to phosphorylate several hexoses. However, while hexokinase II shows an apparent Km for glucose of 1.5 X 10(-4) M with negative cooperativity (nH = 0.4), hexokinase III shows an apparent Km for glucose of 1.5 X 10(-5) M and a positive cooperative effect (nH = 1.5). Furthermore, glucose at concentrations higher than 0.4 mM becomes an inhibitor of hexokinase III. Amino acid analysis of hexokinase type III revealed a low number of the aromatic residues Phe, Tyr, and Trp; this is in agreement with the low extinction coefficient of E1%280nm = 12.5.

Amino Acids↗
PubMed1983

Prenatal prediction of duplication 10q24 leads to qter by gene dosage of GOT1 on uncultured amniotic cells.

Glutamic-oxaloacetic transaminase (GOT1) gene dosage studies were performed on uncultured amniotic cells from a fetus at risk for duplication/deficiency of 10q24 leads to qter, due to maternal translocation t(9;10)(p24;q24). Previous investigations in the same pedigree had shown triplex dosage effect of GOT1 on red blood cells of a 10q24 leads to qter trisomic fetus monitored by midtrimester amniocentesis. In the present pregnancy, the GOT1 activity of amniotic cells exhibited a triplex gene dosage, suggesting duplication of region 10q24 leads to qter in the fetus. The biochemical prediction was confirmed two weeks later by cytogenetic analysis.

Adult↗
PubMed1983

The human liver in extrahepatic cholestasis: ultrastructural morphometric data.

The present study reports the data obtained through a quantitative analysis performed on needle liver biopsies of five jaundiced patients with extrahepatic cholestasis. Whatever the duration of jaundice, the surface density of the smooth endoplasmic reticulum remained in the normal range in all subjects. The surface density of the rough endoplasmic reticulum was variable, showing elevated values in three of the five patients. The surface density of peroxisomes was unchanged with respect to controls. All the subjects exhibited an increase of the surface density of mitochondrial cristae without changes of the outer membrane. These data fail to show evidence of hypertrophy of the smooth endoplasmic reticulum in hepatocytes of human liver during extrahepatic cholestasis. Instead, the increased surface density of the mitochondrial cristae, which has also been previously reported in patients with uncomplicated cholelithiasis, appears as an early and constant phenomenon associated with conformational changes of this mitochondrial component. Such a structural modification might represent an elementary response of the liver cells to alterations in the pathways of synthesis and/or excretion of biliary components.

Cholestasis, Extrahepatic↗
PubMed1983

Study on the lipid composition of rat bile during choleresis induced by diethyl maleate.

Diethyl maleate (DEM) is known to produce a rapid depletion of hepatic glutathione (GSH) and to induce an immediate short-term choleresis in experimental animals. The aim of our investigation was to ascertain in rats the effect of DEM on biliary lipid composition during the increment in bile flow. Biochemical and morphological studies of liver tissue were conducted in parallel. In bile fistula rats, a doubling of bile flow occurred immediately after intraperitoneal injection of DEM (0.7 ml/kg body weight) returning to the basal level at 45 min. Choleresis diluted the total bile acid concentration, without modifying the secretion. The phospholipid concentration was not affected by DEM, resulting in increased output (p less than 0.02 vs. controls). Both cholesterol concentration and output were significantly decreased during DEM-induced choleresis. These changes were promptly reversible together with the return of bile flow to control values. Biochemical determinations failed to show a DEM-induced modification of enzymatic activities of the microsomal drug biotransformation pathway. Instead, morphological studies revealed alterations of the Golgi apparatus in hepatocytes with marked distension of the cisternae in coincidence with choleresis. The results demonstrate that the bile acid-independent choleresis induced by DEM is accompanied by an alternation in biliary lipid secretion possibly related to an interaction of the drug with the cellular or subcellular membranes of hepatocytes.

Animals↗
PubMedDate not supplied

Early structural and functional changes in liver of rats treated with a single dose of valproic acid.

Valproic acid (VPA) is a simple fatty acid largely used as anticonvulsivant agent. Side effects are uncommon, but cases of fatal hepatic failure have been reported. To elucidate the mechanism of VPA-induced hepatotoxicity, the functional and structural changes associated with administration of sodium valproate (NaVPA) to rats (200 or 600 mg per kg, i.p.) were analyzed. NaVPA produced an immediate, dose-dependent and prolonged increase in bile salt-independent bile flow with a decrease in biliary cholesterol and phospholipid output. At 3 and 5 hr, marked ultrastructural changes were evident in hepatocytes, including formation of autophagic vacuoles engulfing altered mitochondria and occasionally peroxisomes. A modest accumulation of lipoprotein particles was evident at 5 hr in the Golgi cisternae. Twelve-hour samples appeared normal. Bile canaliculi and junctional complexes remained unaltered throughout. The changes observed differ from those previously reported with other hydrocholeretics, such as diethylmaleate; they are likely related to hepatic biotransformation of VPA, which undergoes beta and omega-oxidation, and glucuronidation. While VPA-induced choleresis reflects the physiological osmotic effect of the glucuronide excreted in bile, the ultrastructural changes likely reflect interference by VPA with beta-oxidation of endogenous fatty acids and temporary accumulation of transformation products in the mitochondrial matrix.

Animals↗