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Biomedical subjects

M F Sorrell

Publications and source records attributed to M F Sorrell.

At least 127 records · Page 7Linked to original sources
PubMed1984

Effect of ethanol on hepatic secretory proteins.

Both acute and chronic ethanol administration inhibit the secretion of albumin and glycoproteins from the liver. Impairment of posttranslational steps of the secretory process are mainly involved in this secretory defect, although in some instances altered synthesis of the protein moiety may be a factor. Decreased secretion following ethanol administration results in the intrahepatic retention of export proteins. The secretory defect is a consequence of the metabolism of ethanol and is likely mediated via acetaldehyde, although more conclusive proof is still required. The manner by which acetaldehyde impairs the secretory process is unknown, but may be related to its high reactivity with hepatocellular proteins. The specific posttranslational steps or processes involved in the secretory defect are still unclear; however, it appears that the final steps of secretion (post-Golgi events) may be the primary site of impairment. Impaired secretion of proteins from the liver could contribute to altered levels of plasma proteins and hepatomegaly as well as to the liver injury observed in the alcoholic.

Acetaldehyde↗
PubMed1984

Increasing inhibition of hepatic protein secretion by colchicine during development.

Colchicine and other antimicrotubular drugs have been shown to impair plasma protein secretion by fetal rat liver at late gestation (day 21) markedly less than by the mature organ. In the present study, the effect of colchicine on plasma protein secretion by liver slices was determined at several times during rat development. Secretion of [14C]leucine-labeled albumin and [3H]glucosamine-labeled glycoproteins was only minimally impaired (20%) by colchicine (50 microM) on gestation day 19. Inhibition of protein secretion increased to about 40% just before birth and remained unchanged throughout the perinatal period. Inhibition increased thereafter until the maximum effect (75%) was first observed 28 days after birth. Studies in which [3H]-colchicine was used indicated that neither reduced colchicine levels in tissue nor reduced affinity of tubulin for colchicine caused the diminished impairment of secretion in immature liver. These findings suggest that participation of microtubules in liver plasma protein secretion is reduced during development and that full participation is delayed beyond the perinatal period in this species.

Animals↗
PubMed1984

Acute effects of ethanol on hepatic glycoprotein secretion in the rat in vivo.

The in vivo effects of acute ethanol administration on the secretion of plasma glycoproteins and albumin were studied. Ethanol (6 g/kg body wt) was administered intragastrically to nonfasted rats, while control animals received isocaloric glucose. Hepatic protein and glycoprotein secretion in these animals was assessed by determining the rate of appearance of [3H]leucine- and [14C]fucose-labeled proteins into the plasma. Ethanol treatment decreased the secretion of both leucine- and fucose-labeled proteins into the plasma. This inhibition of secretion was accompanied by a corresponding increase in the hepatic retention of both leucine- and fucose-labeled immunoprecipitable secretory proteins. Pretreatment of the ethanol-treated animals with pyrazole, an inhibitor of ethanol metabolism, prevented the inhibition of hepatic protein secretion. These in vivo studies confirm our earlier in vitro findings that acute ethanol administration inhibits the secretion of plasma proteins, resulting in their hepatocellular retention.

Animals↗
PubMed1984

Reduced effect of microtubule inhibitors on hepatic protein secretion in the fetal rat.

Drugs that block the assembly of microtubules inhibit protein secretion by mature hepatocytes. In this study, we ascertained the effects of these drugs on hepatic protein secretion during development. Slices prepared from adult and late-gestation (day 21) fetal rat livers were incubated with colchicine, vinblastine, or podophyllotoxin, and the secretion of [14C]leucine-labeled proteins was then determined. Colchicine (10 microM) decreased trichloroacetic acid-precipitable protein secretion by 65% in adult liver, but only by 31% in fetal liver. A higher (50 microM) concentration of colchicine caused minimal further impairment of secretion in both age groups. Colchicine (10 microM) impaired the secretion of immunoprecipitable albumin to about the same degree as trichloroacetic acid-precipitable proteins in both adult and fetus. Determinations of [3H]colchicine uptake into slices indicated that reduced hepatocellular levels of the drug were not the cause of the diminished effect on protein secretion observed in the fetus. Like colchicine, various concentrations of vinblastine and podophyllotoxin inhibited trichloroacetic acid-precipitable protein and albumin secretion consistently less from the fetal liver (30%-50%) than from the adult liver (50%-75%). These results indicate a reduced dependence on normal microtubule function for protein secretion in the developing liver.

Albumins↗
PubMed1983

Acetaldehyde adducts with proteins: binding of [14C]acetaldehyde to serum albumin.

Acetaldehyde, the immediate oxidation product of ethanol metabolism, was assessed for its ability to bind covalently to a purified protein in solution. Bovine serum albumin (BSA) was used as the model protein incubated in the presence of 0.2 mM [14C]acetaldehyde at pH 7.4 and at 37 degrees C. Acetaldehyde formed both stable and unstable adducts with serum albumin. Unstable adducts were identified following stabilization with the reducing agent sodium borohydride. We examined both types of binding using trichloroacetic acid precipitation, gel filtration, and dialysis as means to separate bound from free acetaldehyde. All three methods of analysis gave comparable results except that the number of stable acetaldehyde adducts with albumin were significantly lower following separation by dialysis. The effects of L-cysteine, L-lysine, and reduced glutathione were assessed for their abilities as competitive reagents to decrease binding of [14C]acetaldehyde to BSA. Addition of cysteine caused a rather dramatic concentration-dependent reduction in [14C]acetaldehyde binding to BSA when compared to that caused by lysine which displayed a relatively mild effect on covalent binding. The presence of glutathione caused a concentration-dependent decrease in protein-bound radioactivity that was stronger than that by lysine but not as effective as cysteine. The ability of each reagent to reverse the formation of preformed acetaldehyde adducts with BSA was also examined. Only L-cysteine effectively decreased the number of unstable acetaldehyde adducts with BSA while stable binding of acetaldehyde remained essentially unaffected by any of the three reagents. These results indicate that acetaldehyde can covalently bind to protein and form unstable as well as stable adducts.

Acetaldehyde↗
PubMed1983

Clinical and biochemical course of alcoholic liver disease following sudden discontinuation of alcoholic consumption.

It has been our impression that clinical deterioration and worsening of liver tests of patients with alcoholic liver disease (ALD) is common immediately following hospitalization and cessation of ethanol intake. In order to determine the frequency of such deterioration and characterize features which may identify those patients who initially deteriorate, we analyzed the standard liver tests and clinical parameters of liver function following hospitalization of 273 cases of ALD, and correlated these with histologic patterns and hospital course. We found that moderate liver test worsening following hospitalization is frequent in patients with ALD, especially alcoholic hepatitis. The presence of alcoholic hyalin in patients with alcoholic hepatitis did not correlate with liver function or frequency of biochemical worsening, but did correlate with mortality. Biochemical deterioration did not correlate with clinical deterioration or mortality, unless complications such as bleeding, sepsis, or pancreatitis occurred. Spontaneous clinical deterioration of our patients in the absence of precipitating factors was rare. We conclude that worsening of liver tests following hospitalization frequently occurs in patients with ALD, does not necessarily imply presence of complications (e.g., biliary obstruction, sepsis, other liver injury), but should suggest the presence of alcoholic hepatitis.

Alanine Transaminase↗
PubMed1983

Effects of chronic ethanol administration on hepatic glycoprotein secretion in the rat.

The effects of chronic ethanol feeding on protein and glycoprotein synthesis and secretion were studied in rat liver slices. Liver slices from rats fed ethanol for 4-5 wk showed a decreased ability to incorporate [14C]glucosamine into medium trichloracetic acid-precipitable proteins when compared to the pair-fed controls; however, the labeling of hepatocellular glycoproteins was unaffected by chronic ethanol treatment. Immunoprecipitation of radiolabeled secretory (serum) glycoproteins with antiserum against rat serum proteins showed a similar marked inhibition in the appearance of glucosamine-labeled proteins in the medium of slices from ethanol-fed rats. Minimal effects, however, were noted in the labeling of intracellular secretory glycoproteins. Protein synthesis, as determined by measuring [14C]leucine incorporation into medium and liver proteins, was decreased in liver slices from ethanol-fed rats as compared to the pair-fed controls. This was the case for both total proteins as well as immunoprecipitable secretory proteins, although the labeling of secretory proteins retained in the liver slices was reduced to a lesser extent than total radiolabeled hepatic proteins. When the terminal sugar, [14C]fucose, was employed as a precursor in order to more closely focus on the final steps of hepatic glycoprotein secretion, liver slices obtained from chronic ethanol-fed rats exhibited impaired secretion of fucose-labeled proteins into the medium. When ethanol (5 or 10 mM) was added to the incubation medium containing liver slices from the ethanol-fed rats, the alterations in protein and glycoprotein synthesis and secretion caused by the chronic ethanol treatment were further potentiated. The results of this study indicate that liver slices prepared from chronic ethanol-fed rats exhibit both impaired synthesis and secretion of proteins and glycoproteins, and these defects are further potentiated by acute ethanol administration.

Animals↗
PubMed1983

Ethanol, hepatocellular organelles, and microtubules. A morphometric study in vivo and in vitro.

The effects of chronic ethanol intoxication on hepatic microtubules are controversial. We, therefore, designed a morphometric study to examine ethanol-induced alterations in microtubules in vivo and in vitro. Using a computer-assisted point-counting system we determined the volume, surface, and length densities of hepatic microtubules, in addition to those of other hepatic organelles. Consistent with previous qualitative descriptions, chronic ethanol feeding caused increases in the volume and surface densities of mitochondria and microsomes. These changes account, in part, for the increased protein content of hepatocytes after chronic ethanol consumption. However, there was no effect on the volume, surface, or length densities of hepatic microtubules, nor on their calculated radii. The structure of isolated bovine brain microtubules after polymerization in vitro was not changed by ethanol or its metabolites, acetaldehyde and acetate. These data indicate that neither chronic ethanol intoxication nor the presence of ethanol, or its metabolites, affects the number or structure of microtubules.

Animals↗
PubMed1983

Binding of metabolically derived acetaldehyde to hepatic proteins in vitro.

Homogenates of rat liver incubated with 10 mM [14C]ethanol were analyzed for acetaldehyde production and for both stable and unstable radiolabeled acetaldehyde adducts with proteins. During incubation, formation of acetaldehyde and of 14C-labeled proteins both increased with time in a parallel manner. Acetaldehyde generation and subsequent formation of radiolabeled proteins were potentiated by supplementation of the cell-free system with NAD+ (1 mM). Cycloheximide (0.1 mM) caused no significant reduction in protein-bound radioactivity, whereas the addition of strong nucleophiles L-cysteine (5 mM) and reduced glutathione (5 mM) each decreased radiolabeling by 50 to 60%. Preheating of crude homogenates at 90 degrees C, prior to incubation with [14C]ethanol profoundly decreased subsequent production of acetaldehyde and formation of 14C-labeled proteins. The results indicate that the major source of protein-bound radioactivity derived from [14C]ethanol oxidation in this system is due to binding of enzymatically derived [14C]acetaldehyde to hepatic proteins.

Acetaldehyde↗
PubMed1982

Effect of antibiotics in the prevention of jejunoileal bypass-induced liver dysfunction.

Administration of antibiotics has been reported to prevent or minimize liver dysfunction in experimental animals having been subjected to jejunoileal bypass, suggesting that jejunoileal bypass-induced liver dysfunction results from production of toxic substances by bacteria in the defunctionalized bowel. However, improved absorption will also prevent bypass-induced liver injury. We studied the effects of tetracycline on the development of bypass-induced liver dysfunction and compared it to the mucosal adaptation of the intact bowel after bypass. After 6 weeks, rats subjected to bypass but not given antibiotics had decreased levels of serum triglycerides, hepatic cytochrome P-450, and hepatic pentobarbital hydroxylase. Evaluation of intestinal mucosal hyperplasia after bypass indicated that animals given antibiotics after bypass developed greater increases in mucosal DNA content, mucosal protein, and mucosal weight than bypassed animals not receiving antibiotics. We speculate that the beneficial effects of antibiotic administration on liver function after bypass may be a result of improved absorption.

Animals↗
PubMed1981

Etiology of jejunoileal bypass-induced liver dysfunction in rats.

Several recent studies suggest that jejunoileal bypass-induced liver disease results from malabsorption of essential nutrients. However, in experimental animals, resection of the defunctionalized bowel substantially reduces bypass-induced liver injury. Such models are often used to support the theory that bacteria in the defunctionalized bowel produce toxic substances which result in liver damage. We used a rat model to first explore the effects of intestinal bypass vs resection on various parameters of liver injury, and subsequently compared these findings to the effect of both bypass and resection on mucosal adaptation in the remaining intact bowel after each procedure. Bypassed animals had lower levels of hepatic cytochrome P-450, glucose-6-phosphatase, pentobarbital hydroxylase, and serum triglycerides than did animals undergoing resection of defunctionalized bowel. Concurrently, resected animals had much greater increases in mucosal weight, DNA content, and protein content in the intact bowel than did bypassed animals. We speculate that the beneficial effects of resection of bypassed bowel on liver function may be a result of increased mucosal hyperplasia in resected animals, rather than elimination of production of toxic substances in the defunctionalized bowel.

Animals↗
PubMed1981

Immunologic aspects of alcoholic liver disease.

Continuing hepatic injury despite cessation of ethanol intake has suggested a potential role for altered humoral and cellular immunity in the pathogenesis of alcoholic liver disease. Variation of cell-mediated response has been observed most commonly in patients with alcoholic hepatitis. These alterations include decreased mitogen response in vitro, reduction of circulating T-cell numbers with a corresponding increase of intrahepatic T-cells, lymphokine production in vitro in response to isolated alcoholic hyalin (Mallory bodies), and in vitro evidence of increased spontaneous cell-mediated cytotoxicity. Fewer immunologic alterations are detected in patients with alcoholic fatty liver or cirrhosis. At present, these observations have not established a definite causal relationship between ethanol-induced liver injury and immunologic mechanisms. Studies utilizing in vitro correlates of cellular immunity in alcoholics are carried out after development of hepatic injury. To establish the role of humoral and cellular immune events in the pathogenesis of alcoholic liver injury will require development of a suitable animal model.

Granulocytes↗