Effects of the diazafluoranthen derivative AC-3579 on rat liver. B - Morphological and biochemical study of the intracellular distribution of glucose-6-phosphatase

Administration of the diazafluoranthen derivative AC-3579 induces in rat liver, the hypertrophy of the smooth endoplasmic reticulum (SER) and the formation of lamellate cytosomes. The cytochemical demonstration of one microsomal marker, glucose-6-phosphatase, was performed in treated liver cells in situ and was correlated to biochemical determinations performed in subcellular fractions isolated by differential and gradient centrifugation. While glucose-6-phosphatase is evenly distributed inside the liver lobule in the control, it presents a heterogeneous localization within the lobule of treated animals. The cytochemical reaction appears considerably decreased in the centrolobular regions, when compared to the perilobular ones. Ultrastructural examination of the centrolobular hepatocytes of treated animals shows that the cytochemical reaction products are irregularly dispersed within the anastomosed tubules of the hypertrophied SER. A discontinuous reaction is discerned in the cisternae of concentric whorled membranes. The specific activity of glucose-6-phosphatase in liver homogenate of treated rats was decreased by about 20% as compared to the controls. After 4 or 8 days AC-3579 treatment, no glucose-6-phosphatase reaction was detected in the lamellate cytosomes, neither in situ nor in their isolated form. The absence of this microsomal marker in the cytosomal membranes did not exclude their SER origin, since an intense hydrolytic degradation takes place inside the cytosomes as demonstrated by the high concentration of acid phosphatase revealed in these organelles after purification by gradient centrifugation.SCOPUS: NotDefined.jinfo:eu-repo/semantics/publishe

Effects of the diazafluoranthen derivative AC-3579 on rat liver. A - Isolation and characterization of lamellate cytosomes and subcellular localization of the drug

Lamellate cytosomes induced in rat hepatocytes by the diazafluoranthen derivative AC-3579 were isolated and purified by centrifugation of a resuspended 10,000 g pellet on a discontinuous sucrose gradient. Well preserved purified lamellate cytosomes similar to those observed in liver cells in situ were collected at a density between 1.10-1.14. In purified lamellate cytosomes, phospholipid/protein and cholesterol/phospholipid ratio's were comparable to those of the smooth microsomes of treated animals. The pattern of individual phospholipids of the cytosomes was similar to that of the whole homogenate. These results suggest that the cytosomal material corresponds to sequestered smooth endoplasmic reticulum membranes. After administration of labelled AC-3579, the specific radioactivity was selectively increased in fractions containing the lamellate cytosomes. These data favour the hypothesis that AC-3579 induced cytosomes result from the formation of a complex between the drug and the phospholipids. In smooth microsomes of treated rats, the phospholipid/protein ratio was increased and the cholesterol/phospholipid ratio markedly decreased as compared to the controls. This indicates that the drug induces alterations in the biochemical composition of the membranes.SCOPUS: NotDefined.jinfo:eu-repo/semantics/publishe

An experimental study of the "cationized protein disease" in the dog

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The Pathogenicity of Cationized Albumin in the Dog

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Pathogenicity of cationized albumin in the dog: renal and extrarenal effects

The effects of 21 cationized serum albumin samples of various degrees of cationization on renal function were studied in the dog. The samples were perfused intra- aortically to obtain preferential perfusion of the left kidney in 25 dogs. Standard clearance techniques were used, associated in six dogs with sieving studies of 125I-labelled polyvinylpyrrolidone (125I-PVP) and with an extensive morphological study in 15 dogs. Renal effects were observed. (a) Renal effects in left kidneys. The perfusion with weakly cationized albumin (group 1) produced moderate proteinuria associated with the deposition of cationized albumin on the anionic sites of the basement membrane. Glomerular filtration rate (GFR) was unaltered. Perfusion with highly cationized samples (group 2) produced more severe proteinuria and a significant decrease in GFR. Glomerular permeability to 125I-PVP increased. Perfusion with the four samples of highest pI (group 3) was followed by anuria. (b) Renal effects in right kidneys. A retarded mild proteinuria appeared only in group 2 and group 3 animals without alteration of GFR. All the kidneys (group 1 included), with the exception of two (group 3), showed deposition of the protein in the anionic sites. The following extrarenal effects were observed essentially in group 2 and group 3 animals: erythrocyte agglutination and haemolysis, platelet aggregation and thrombocytopenia, and a decrease in plasma fibrogen level due to fibrinogen precipitation. These effects produced progressive obstruction in the glomerular capillaries, thus explaining the occurrence of anuria. The structural damage in group 2 and group 3 left kidneys bears remarkable resemblance to that observed in the fulminant form of the human so-called 'haemolytic-uraemic syndrome'. The neutralization alone of the fixed negative charges in the glomerular wall appears to produce only mild proteinuria, whereas the various extrarenal effects combine to produce more severe proteinuria associated with functional alteration and vascular obstruction.info:eu-repo/semantics/publishe