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M F Sorrell

Publications and source records attributed to M F Sorrell.

177 records · Page 10Linked to original sources
PubMedDate not supplied

Effect of ethanol on the synthesis and secretion of hepatic secretory glycoproteins and albumin.

The effects of ethanol on the synthesis and secretion of serum glycoproteins and albumin, a nonglycosylated protein, were studied in rat liver slices. Serum glycoproteins and albumin were determined by immunoprecipitation from either the incubation medium or from the washed slices. When ethanol (10 mM) was present in the incubation medium, [14C]glucosamine incorporation in secretory glycoproteins was decreased. This inhibitory effect was, however, much greater in the secretory proteins released into the medium than in those retained in the liver slices. Similar inhibitions by ethanol were also observed when leucine or valine were used as a label for either total export proteins or albumin. Since ethanol impaired protein synthesis, and inhibitor of protein synthesis, cycloheximide, was used so that both the control and ethanol-treated slices had identical pools of protein acceptors available for glycosylation. When cycloheximide alone was added to the slices, glucosamine radioactivity of secretory glycoproteins was equally reduced in both the medium and the liver. When cycloheximide and ethanol were both present, decreased appearance of glucosamine-labeled proteins in the medium was observed when compared to the slices containing cycloheximide alone; however, radioactivity of secretory glycoproteins retained in the liver was elevated. Ethanol also decreased the appearance of fucose-labeled glycoproteins in the medium without altering fucose incorporation into the total pool of secretory glycoproteins. The effects of ethanol on hepatic protein secretion independent of its effect on synthesis were further determined by prelabeling proteins with either [14C]leucine or [14C]fucose. Ethanol impaired the secretion of these prelabeled proteins into the medium. The results of this study show that ethanol impairs both the synthesis and secretion of secretory glycoproteins and albumin.

Albumins↗
PubMedDate not supplied

Covalent binding of acetaldehyde selectively inhibits the catalytic activity of lysine-dependent enzymes.

Hepatic ethanol metabolism generates the reactive intermediate, acetaldehyde, which binds to proteins. The binding of acetaldehyde to purified enzymes was determined in order to ascertain whether such binding altered their catalytic functions. [14C]Acetaldehyde was incubated with alcohol dehydrogenase, glucose-6-phosphate dehydrogenase, lactate dehydrogenase and RNase A, each at 37 degrees C (pH 7.4). In some reactions, sodium cyanoborohydride was included for stabilization of Schiff bases, formed as a result of the reaction between acetaldehyde and the amino groups of the enzymes. Portions of each reaction mixture were removed for determination of stable and total (stable plus borohydride-reducible) adducts. Alcohol dehydrogenase and lactate dehydrogenase were not inhibited by adduct formation. Glucose-6-phosphate dehydrogenase and RNase, the activities of which depend on a lysine residue at their catalytic sites, were inhibited in a dose- and time-dependent manner. The degree of inhibition directly correlated with total adduct formation. Phosphate, known to inhibit binding to the active site lysine of RNase, prevented the inhibition of catalytic activity caused by adduct formation. These findings indicate that the binding of acetaldehyde to lysine at the catalytic site can inhibit enzyme activity.

Acetaldehyde↗
PubMedDate not supplied

Role of acetaldehyde in the ethanol-induced impairment of hepatic glycoprotein secretion in the rat in vivo.

Ethanol administration inhibits hepatic protein and glycoprotein secretion. Previous studies have shown that the metabolism of ethanol is required for this effect. Experiments were designed to determine whether acetaldehyde, the first metabolite of ethanol oxidation, mediated the ethanol-induced secretory defect in rats with normal and stimulated (inflammation-induced) rates of hepatic protein secretion. This study used cyanamide, an aldehyde dehydrogenase inhibitor, to correlate enhanced acetaldehyde levels with an increased ethanol-induced inhibition of hepatic protein secretion. Inflammation was induced by turpentine 24 hr prior to cyanamide (5 mg per kg body weight) or saline pretreatment. Nonfasted rats were intragastrically gavaged with ethanol (4 to 6 gm per kg body weight) or isocaloric glucose 1 hr following pretreatment. [3H]Fucose and/or [14C]leucine were injected intravenously 2 hr following intubation. With elevated levels of acetaldehyde, the ethanol-induced impairment of secretion of labeled proteins and their parallel retention in the liver were markedly potentiated. During inflammation, this inhibition of secretion by ethanol was maintained and further increased with cyanamide pretreatment. These results indicate that the ethanol-induced impairment of hepatic glycoprotein secretion is mediated by acetaldehyde in both normal and inflammation-stimulated animals.

Acetaldehyde↗
PubMedDate not supplied

Zonal differences in ethanol-induced impairments in hepatic receptor binding.

We have previously shown ethanol-induced defects in receptor-mediated endocytosis of asialoorosomucoid (ASOR), epidermal growth factor (EGF), and insulin in isolated rat hepatocytes. The present study was undertaken to compare the binding of these three ligands in both Zone 1 (periportal [PP] region) and Zone 3 (perivenule [PV] region) of rat liver. Cells from the PV region of ethanol-fed animals bound significantly less EGF (40% decrease) than did cells from the same area in control rats. EGF binding was decreased to a lesser extent (15-25%) in PP cells from ethanol-fed animals compared to controls. When binding of ASOR was examined, ethanol feeding significantly impaired binding in both PP cells (30-35% decrease) and PV cells (50-55% decrease), again showing a greater ethanol-induced impairment in the PV region. Insulin binding in ethanol animals was decreased by 20-25% in both regions compared to controls. In addition, we found that ASOR receptor recycling was impaired to a greater extent in the PV than in the PP region of liver after ethanol feeding, indicating selective impairment of receptor function in the centrilobular region of the liver.

Animals↗