Expression of the multidrug-resistant gene in hepatocarcinogenesis and regenerating rat liver

Preneoplastic and neoplastic liver nodules and hepatocytes isolated from regenerating rat liver have been shown to be resistant to a broad range of carcinogenic agents. This phenomenon was studied by measuring the expression of the multidrug-resistant (mdr) gene in normal liver cells and in preneoplastic and neoplastic nodules and regenerating liver. Levels of messenger RNA for the mdr gene, which encodes P-glycoprotein, were elevated in both preneoplastic and neoplastic lesions. Expression of the mdr gene also reached high levels in regenerating rat liver 24 to 72 hours after partial hepatectomy. These results show that the expression of the mdr gene can be regulated in liver and is likely to be responsible for part of the multidrug-resistance phenotype of carcinogen-initiated hepatocytes and regenerating liver cells.     

L-asparaginase induced immunosuppression: inhibition of bone marrow derived antibody precursor cells

The cooperation between bone marrow and thymus cells in restoring the hemolytic antibody response to sheep erythrocytes in immunosuppressed recipients was markedly inhibited when donor mice were treated with L-asparaginase, a known inhibitor of lymphocyte function. The marrow cell population was shown to be a major target for the immunosuppressive activity of asparaginase, since thymus cells from enzyme-treated animals interacted with marrow cells from normal animals to generate immunocompetent cells.     

Turnover of rat liver tyrosine transaminase: stabilization after inhibition of protein synthesis

Turnover of the rat liver tyrosine transaminase in vivo was measured by a label and chase procedure under conditions where the amount of enzyme undergoes no change. Half-life of the (14)C-labeled enzyme in this basal condition was found to be 1.5 +/- 0.3 hours. Inhibitors of protein synthesis (cycloheximide or puromycin) do not appreciably influence the basal enzyme level over a 5-hour period, although these drugs will block hormonal induction of this enzyme. In pulse-labeling experiments, cycloheximide blocked transaminase synthesis almost completely. The conclusion that enzyme degradation, as well as synthesis, must be blocked when protein synthesis is stopped was confirmed in experiments showing that labeled enzyme is stable in the liver of rats treated with cycloheximide The participation of a continuously synthesized polypeptide in the degradative phase of transaminase turnover is suggested.     

Hemopoietic colony-forming units in regenerating mouse liver: suppression by anticoagulants

After hepatic injury induced by carbon tetrachloride, mitotically active hematopoietic cells of nonhepatic origin localize in the liver as judged by an increase in colony-forming nodules in the spleens of lethally irradiated recipient mice on intravenous injection of cells from these livers. The administration of warfarin suppresses the localization of colony-forming units in the regenerating liver by inhibiting the coagulation mechanism of the donor animals.     

Glycerol metabolism in the human liver: inhibition by ethanol

Glycerol is metabolized predominantly in the liver, the first step presumably being phosphorylation to alpha-glycerophosphate. When ethanol is present in the blood the rate of glycerol uptake by the splanchnic organs is reduced to about one-third of the control value. At the same time glycerophosphate accumulates in the liver. Hepatic blood flow and oxygen consumption are not influenced by the combined infusion of glycerol and ethanol. The phenomenon may be connected with the increased concentration of the reduced form of diphosphopyridine nucleotide present in the liver during ethanol metabolism.     

Hormone-sensitive adenyl cyclase: cytochemical localization in rat liver

An electron microscopic procedure has been developed, using rat liver, for the localization of hormone-sensitive adenyl cyclase. Isoproterenol-sensitive adenyl cyclase is located almost exclusively in the parenchymal cells. In contrast, glucagon-sensitive adenyl cyclase is located primarily in the reticulo-endothelial cells but is also present in parenchymal cells. Sodium fluoride-sensitive adenyl cyclase is found in both cell types.     

Feedback inhibition of key glycolytic enzymes in liver: action of free fatty acids

Increasing concentrations of sodium octanoate were progressively inhibitory to the activities of glucokinase, hexokinase, phosphofructokinase, and pyruvate kinase. Glucose-6-phosphate and 6-phosphogluconate dehydrogenases were also markedly inhibited. Other enzymes of carbohydrate metabolism such as lactate dehydrogenase, phosphohexose isomerase, and fructose-1,6-diphosphatase were not decreased. Among the key glycolytic enzymes, the inhibition of pyruvate kinase by the fatty acid was most marked. The biological significance of the inhibition of the key glycolytic enzymes is interpreted as a feedback inhibitory mechanism in regulation of fatty acid biosynthesis. The mechanism may function for rapid adaptation by which the organism can use the fatty acid level as a metabolic directional switch in decreasing glycolysis and turning on gluconeogenesis.     

Actinomycin D and Hydrocortisone: intracellular binding in rat liver

DNA was found to be the major intracellular binding site for labeled actinomycin D administered in vivo. In analogous studies, hydrocortisone did not bind to nuclear structures. Furthermore, following the administration of actinomycin D, a highly positive correlation was found between the RNA content of the nucleus and the ability of the nucleus to synthesize RNA.     

Vitamin A: concentration in the rat liver Golgi apparatus

Vitamin A compounds (principally as retinyl esters) are concentrated in Golgi apparatus fractions from rat liver. The amounts vary with the vitamin A status of the liver and show an inverse relation to the concentration of ubiubinone. The results suggest a specific role of the Golgi apparatus in the mobilization or action, or both, of vitamin A compounds.     

Ethylene formation in rat liver microsomes

Reduced triphosphopyridine nucleotide and pyrophosphate-dependent peroxidation of lipids in rat liver microsomes were coupled to the generation of ethylene in the presence of cuprous ions. This system suggests a model for the biogenesis of ethylene in cells.     

Synaptogenesis in the rat cerebellum: effects of early hypo- and hyperthyroidism

The number of synapses in the molecular layer of the rat cerebellum is reduced by early hypo-and hyperthyroidism within 30 days. Hypothyroidism retards synaptogenesis after 10 days, while hyperthyroidism accelerates synaptogenesis initially, but by 21 days the number of synapses is reduced. The sensitivity of developing synapses to thyroid hormone may permit analysis of the events triggering synaptogenesis.     

Turnover of ribosomal RNA in rat liver

After a single injection of radioactive orotic acid and a "chase" of nonradioactive precursor, the specific activity of ribosomal RNA in rat liver decreases logarithmically at a rate corresponding to a half-life of about S days. The possible significance of this result is discussed with regard to control of protein synthesis.     

Plasma membranes of rat liver: isolation of lipoprotein macromolecules

Three high-denisity lipoprotein classes and one protein were separated from rat-liver plasma in membranes that had been treated with mild sonic oscillation. The lipoproteinis were separated and identified by techniques in which ultracentrifugation was used. Enzyme markers and electron-microscopic examination revealed membrane preparations essentially free of contaminating cellular partictulates.     

Hepatic microsomal enzymes in man and rat: induction and inhibition by ethanol

The feeding of ethanol increased significantly the activities of hepatic pentobarbital and benzpyrene hydroxylases in rats, and, in human volunteers, doubled pentobarbital hydroxylase activity. In vitro ethanol inhibited aniline, pentobarbital, and benzpyrene hydroxylases. These data may explain, at least in part, the increased tolerance of alcoholics to sedatives when sober, and the enhanced sensitivity to sedatives when inebriated.     

Diurnal rhythm in endoplasmic reticulum of rat liver: electron microscopic study

Electron microscopy of rat hepatocytes revealed a diurnal variation in the relative amounts of endoplasmic reticulum structures and regional differences in their distribution within the hepatic lobule. The diurnal changes in smooth and rough endoplasmic reticulum structures were compared with the diurnal changes in the hepatic microsomal enzyme hexobarbital oxidase. In the control group, at the time when enzyme activity was maximum, the amount of smooth endoplasmic reticulum was also maximum and vice versa. When the enzyme rhythm was abolished, as in blinded rats, the diurnal rhythm in the endoplasmic reticulum was also abolished.     

Regulation of mitosis in Stentor coeruleus

When Stentor coeruleus was cut into anterior and posterior halves, the micronuclei in the posterior half underwent mitosis about 5 to 6 hours later, as shown in stained preparations. It is suggested that the division of the micronuclei was initiated by metabolic changes which resulted from the lack of adoral membranelles.     

Phosphorylase: a new isozyme in rat hepatic tumors and fetal liver

A third set of phosphorylase a and b isozymes, distinguishable kinetically and immunologically from liver and muscle forms, is present in various rat hepatomas, and is also present, together with the adult liver form, in fetal rat liver. This is one of several striking examples of suppression of isozymes of adult liver coupled with the appearance of fetal isozymes in hepatomas.     

Histochemical demonstration in rat of monoamine oxidase inhibition of beta-phenyl-isopropyl hydrazine

A histochemical method for demonstration of monoamine oxidase activity was found to be almost as sensitive as a biochemical method when used for revealing total inhibition of monoamine oxidase in rat tissues after administration of beta-phenyl-isopropyl hydrazine. The histochemical method is of special value in the study of monoamine oxidase inhibition in the complex structures of the brain.