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H Orrego

Publications and source records attributed to H Orrego.

At least 55 records · Page 3Linked to original sources
PubMed1985

Increased loss and decreased synthesis of hepatic glutathione after acute ethanol administration. Turnover studies.

The effect of acute ethanol administration on rates of synthesis and utilization of hepatic glutathione (GSH) was studied in rats after a pulse of [35S]cysteine. A 35% decrease in hepatic GSH content 5h after administration of 4 g of ethanol/kg body wt. was accompanied by a 33% increase in the rate of GSH utilization. The decrease occurred without increases in hepatic oxidized glutathione (GSSG) or in the GSH/GSSG ratio. The rate of non-enzymic condensation of GSH with acetaldehyde could account for only 6% of the rate of hepatic GSH disappearance. The increased loss of [35S]GSH induced by ethanol was not accompanied by an increased turnover; rather, a 30% inhibition of GSH synthesis balanced the increased rate of loss, leaving the turnover rate unchanged. The rate of acetaldehyde condensation with cysteine in vitro occurred at about one-third of the rate of GSH loss in ethanol-treated animals. However, ethanol induced only a minor decrease in liver cysteine content, which did not precede, but followed, the decrease in GSH. The characteristics of 2-methylthiazolidine-4-carboxylic acid, the condensation product between acetaldehyde and cysteine, were studied and methodologies were developed to determine its presence in tissues. It was not found in the liver of ethanol-treated animals. Ethanol administration led to a marked increase (47%) in plasma GSH in the post-hepatic inferior vena cava, but not in its pre-hepatic segment. Data suggest that an increased loss of GSH from the liver constitutes an important mechanism for the decrease in GSH induced by ethanol. In addition, an inhibition of GSH synthesis is observed.

Acetaldehyde↗
PubMed1985

Lack of changes in diene conjugate levels following ethanol induced glutathione depletion or hepatic necrosis.

Acute administration of 5 g/kg ethanol resulted in a 35% reduction of glutathione levels but not in increases in lipoperoxidation as measured by diene conjugate levels in mitochondria or in microsomes. Administration of diethylmaleate which markedly decreased glutathione levels by 85% did not render the livers susceptible to lipoperoxidation after ethanol administration. Chronic alcohol administration did not result in detectable changes in diene conjugates with respect to isocaloric sucrose treatment. Liver necrosis when induced by anemia in rats chronically treated with ethanol was not accompanied by increases in diene conjugate levels.

Animals↗
PubMed1984

Hypermetabolic state and hypoxic liver damage.

The concept of a hypermetabolic state to explain metabolic tolerance to ethanol grew from the recognition that the rate of alcohol metabolism is, in general, limited by the rate at which mitochondria can reoxidize reducing equivalents and thus by the rate at which oxygen can be consumed by the liver. This relationship appears to be most important in conditions in which the alcohol dehydrogenase (ADH)/QO2 ratio is high and is not in conflict with observations suggesting that ADH can, under certain conditions, constitute a rate-determining step for ethanol metabolism in rodents. Liver preparations from animals fed alcohol chronically, in which an increase in ethanol metabolism is shown, consume oxygen at higher rates. This effect, concerning which there is discrepancy among investigators, depends on the type of preparation. Thyroid hormones play a permissive role in the development of the hypermetabolic state, while increased circulating levels of these hormones are not required. Antithyroid drugs inhibit both metabolic tolerance in vivo and the hypermetabolic state. While the hypermetabolic state requires an increased ATP utilization in the form of an adenosine triphosphatase, or an inhibition of ATP synthesis, the different mechanisms proposed for such an effect do not quantitatively account for the increases in oxygen consumption. In humans and animals chronically exposed to ethanol, but withdrawn, oxygen tensions in blood leaving the liver are significantly reduced. In some situations, low oxygen tensions in zone 3 of the hepatic acinus can reach critical hypoxic levels and may lead to cell necrosis. Studies in which the effectiveness of propylthiouracil is tested in human alcoholic hepatitis are discussed.

Adenosine Triphosphate↗
PubMed1983

On the characteristics of alcohol-induced liver enlargement and its possible hemodynamic consequences.

Chronic consumption of alcohol leads to an increase in liver weight, primarily due to an increase in hepatocyte volume. About 50-60% of such an increase is due to an increase in intracellular water. Accumulation of intracellular K+ osmotically accounts for about one half of the increase in intracellular water, while an increase in soluble proteins plays only a minor role in such an increase in cell volume. The increase in intracellular water is accompanied by a relative reduction in water in the extracellular space, probably due to compression of the extracellular volume by the enlarged hepatocytes. It is suggested that such an increase in hepatocyte size, with an attending reduction of the extracellular volume, results in an increased resistance to blood flow through the liver and thus in an increase in portal pressure. In alcoholics, portal and intrahepatic pressure correlate with cell size both in cirrhotics (r = 0.79) and in non-cirrhotics (r = 0.74), thus suggesting that cell enlargement plays a major role in the production of portal hypertension in the alcoholic.

Alcoholism↗
PubMed1983

Effect of alcohol on propylthiouracil disposition.

We examined the effect of ethanol on propylthiouracil (PTU) disposition in normal subjects and a rabbit. The drug is metabolized by conjugation. In six normal subjects 19.2 gm oral ethanol, taken either with or two hr after 300 mg PTU, did not change maximum concentration, time to maximum concentration, or total or free AUC of PTU. Pretreatment with ethanol and supplementation to keep blood ethanol concentration above 800 mg/l for 8 hr also did not alter PTU disposition. In the rabbit, the infusion of ethanol (8.81 mg/min) 4 hr after the beginning of an intravenous infusion of PTU 0.05 mg/min did not alter the plasma concentration profile. These results indicate that short-term ethanol dosing does not affect PTU disposition and therefore dosage adjustment is not necessary in patients who drink alcohol.

Administration, Oral↗
PubMed1983

Calcium requirement for anoxic liver cell injury.

There is disagreement as to whether Ca2+ entrance into the cell constitutes a final common pathway in cell death by a variety of injurious conditions. Pre-necrotic lesions and leakage of lactate dehydrogenase were induced both in isolated perfused rat livers and in freshly isolated hepatocytes by short exposure to anoxic conditions. Removal of Ca2+ from the media markedly reduced cell damage induced by anoxia in the perfused liver preparation but not in freshly isolated hepatocytes. Data obtained support the hypothesis that Ca2+ ions play a role in the process of cell death in intact preparations and possibly in vivo, and suggest that mechanism of cell necrosis may be different in the perfused liver than in freshly isolated suspended hepatocytes.

Animals↗
PubMed1982

Alcohol-induced hepatomegaly: pathogenesis and role in the production of portal hypertension.

Hepatomegaly after chronic alcohol consumption results from an increase in cell size and not in cell number. About 50--60% of the increase in liver weight is accounted for by an increase in intracellular water, while extracellular water remains constant. Therefore, a substantial reduction in the ratio of extracellular to intracellular water occurs. Intracellular potassium can osmotically account for 40--50% of the excess water retained in the hepatocytes. It is proposed that an increase in hepatocyte size after chronic alcohol consumption compresses vascular-sinusoidal pathways. This results, after a threshold in cell size is exceeded, in increased intrahepatic and portal pressure. Possible factors responsible for the threshold are proposed. By applying the concept that animal cells act as osmometers, a new in vitro model has been developed to study the relationship between cell enlargement and portal pressure. In this model, the existence of a threshold and the generation of portal hypertension associated with hepatocyte enlargement have been demonstrated. In humans with alcoholic liver disease, a threshold in hepatocyte size enlargement (1600--1700 micrometer 2) before pressures were increased was also observed. In these patients, a strong correlation was also found between hepatocyte size and intrahepatic pressure. The same correlation occurs regardless of the presence or absence of cirrhosis, therefore suggesting that a major determinant of portal hypertension in cirrhosis is cell size and not the existence of nodules of fibrous septa. The higher portal pressures found in cirrhotics may be explained by the fact that these patients have larger hepatocytes.

Animals↗
PubMed1981

Low-molecular-weight polyethylene glycol as a probe of gastrointestinal permeability after alcohol ingestion.

Gastrointestinal permeability has been assessed previously by the excretion of PEG-400, which consists of inert molecules that are neither degraded nor metabolized and are excreted intact in the urine. We report here the effects of alcohol on gastrointestinal permeability using PEG-400. Ten grams of PEG-400 dissolved in 60 ml of water were given to 12 intoxicated alcoholics (mean blood alcohol: 2406 mg/liter). The mean urinary excretion of PEG-400 in the following 6 hr was 3.75 +/- 0.3 g SEM. When repeated after sobering up (mean elapsed time: 45 hr), all except one subject showed a decrease in PEG-400 excretion (mean: 2.08 +/- 0.2 g) (P less than 0.001). Similar experiments were conducted in two series with 12 normal controls. (1) In 7 subjects the administration on consecutive days of (a) PEG-400 (10 g) alone, (b) 10.2 g (0.42 mol) of ethanol plus PEG-400 (10 g), (c) PEG-400 (10 g) alone, and (d) PEG-400 (10 g) plus a diuretic (40 mg furosemide) resulted in the following values of PEG-400 excretion in urine: (a) 2.12 +/- 0.3 g; (b) 3.5 +/- 0.3 g, P less than 0.005; (c) 2.02 +/- 0.4, NS; and (d) 2.2 +/- 0.2 g, NS. (2) In the second experiment (5 subjects) the administration on subsequent days of (a) PEG-400 (10 g) + 0.42 mol of urea; (b) PEG-400 (10 g) + 19.2 g ethanol; (c) PEG-400 (10 g) + 0.42 mol of urea resulted also, as in the previous experiment, in increased urinary excretion of PEG-400 after the solution (b) containing ethanol (P less than 0.001). Peak serum levels of PEG-400 were (a) 0.094 +/- 0.01 g/liter; (b) 0.152 +/- 0.02 g/liter (P less than 0.05); and (c) 0.095 +/- 0.01 (P less than 0.05). The ratio of urea--creatinine clearance and urinary volumes were the same in the three periods. Therefore, PEG-400 excretion was not related to changes in urinary clearance or in volume, since the furosemide increased the volume but not PEG-400 excretion. It is concluded that ethanol increases the permeability of the gastrointestinal tract as measured by the PEG-400 test, both in chronic alcoholics during intoxication and in nonalcoholics after a small dose of ethanol. The permeability alteration is transient once ethanol ingestion stops.

Adult↗
PubMed1981

Hepatocyte demand and substrate supply as factors in the susceptibility to alcoholic liver injury: pathogenesis and prevention.

In conclusion, the studies presented suggest that two factors commonly occurring in the alcoholic, namely, an increased rate of ethanol metabolism and hepatomegaly, may have important pathogenic implications in alcoholic liver disease. An increased rate of ethanol metabolism is linked to a greater oxygen demand, thus resulting in greater susceptibility to hypoxia in Zone 3 of the liver acinus, a factor which might be responsible for hepatocellular necrosis in alcoholic hepatitis. Propylthiouracil has been shown to have a protective effect against hypoxic necrosis in alcohol-fed animals and has been found to be most effective in accelerating the rate of recovery of alcoholics with active liver disease. On the other hand, hepatocyte expansion in hepatomegaly, in the face of a semi-rigid liver capsule, leads to constriction of extracellular volume and to an increase in intrahepatic and portal pressure. The latter, in turn, could produce a variety of haemodynamic alterations as those found in the alcoholic. To what extent the mechanisms described are responsible for or might add to the myriad of other disturbances observed in alcoholic disease should be further analysed.

Animals↗
PubMed1981

[Practical introduction of the medical student to biomedical research].

This paper reports on a course being given in the Institute of Biological Sciences of the Catholic University of Chile in which third-year medical students are introduced to biomedical research participating in it as assistants. The primary aim of the course is instruction in the scientific method on a tutorial basis. The course is elective; it is directed and coordinated by a professor, and conducted by tutoring professors engaged in research. The student chooses a research project from a list presented by the tutoring professors through the professor in charge. His performance is evaluated on the basis of his participation in the work itself and discussions of it, his presentation to the final session of the course, and his manuscript. In the last ten years, 47 per cent of the third-year medical students have taken and passed this course. Performance has been on the rise as shown by the fact that the results of ten of the research projects conducted in the course have been published in the last six years. A student who wishes to continue in a research project may compete for the position of student assistant offered by the School of Medicine, in which post he is enabled to complete his scientific training and the project he had started in.

Chile↗
PubMed1981

Correlation of intrahepatic pressure with collagen in the Disse space and hepatomegaly in humans and in the rat.

In 70 alcoholic patients the amount of collagen in the space of Disse was compared, using an electron microscopic graded score, to the height of the intrahepatic pressure. A highly significant correlation was found between the amount of collagen and intrahepatic pressure in the group as a whole (r = 0.84; p < 10(-6)), as well as in subgroups of 30 alcoholic patients with normal livers or steatosis (r = 0.83; p < 10(-6)), 9 patients with alcoholic hepatitis (r = 0.81; p < 0.01), and 31 with cirrhosis (r = 0.86; p < 10(-6)). A nonparametric correlational analysis for the complete group also showed a significant relationship (rho = 0.85; p < 10(-6)) between collagen scores and intrahepatic pressure. In 60 patients hepatocyte surface area was measured in the biopsies. In these, hepatocyte surface area significantly correlated with intrahepatic pressure (r = 0.68; p < 10(-7)). No correlation was found between intrahepatic pressure and fat, alcoholic hyalin, or terminal hepatic vein sclerosis. Only with necrosis (r = 0.38; p < 0.001) and inflammation (r = 0.29; p < 0.05) was there a significant relationship with intrahepatic pressure. Chronic ethanol administration for 4 wk in liquid diets to young Wistar rats produced a 50% hepatomegaly due to an increase in hepatocyte size. Intrahepatic pressure in the rats receiving alcohol (19.3 +/- 2.3 mmHg) was significantly higher than in the controls on sucrose (10.4 +/- 0.9 mmHg) (p < 0.01). A highly significant correlation was found between hepatocyte surface area and intrahepatic pressure (r = 0.70; p < 0.005). There was no increase in collagen in the Disse space in these animals. Therefore, hepatomegaly in the absence of an increase in collagen in the Disse space may result in increased intrahepatic pressure. These studies may indicate a sequence of events: hepatomegaly, portal hypertension, and collagenization in the Disse space, which could occur in alcoholic liver disease.

Alcoholism↗
PubMed1981

Long-term ethanol administration and short- and long-term liver regeneration after partial hepatectomy.

The purpose of this study was to determine whether long-term ethanol consumption affects the long-term regeneration of the liver after partial hepatectomy and to study whether the metabolic demands imposed on the liver by the regenerative process accentuate liver damage produced in the liver by ethanol. Animals fed alcohol (35% of total calories) in liquid diets over time were partially hepatectomized (68% removal) and then were given ethanol-containing diets until complete liver restitution. They were studied at 24 hr and at 7 and 14 days. At these times, prior and continued ethanol administration did not result in changes in total DNA restituted, percent of cells undergoing mitosis, or incorporation of 3H-thymidine into DNA as determined chemically and by autoradiography. After partial hepatectomy, ethanol-fed animals showed a reduction in both DNA and proteins per gram of liver. However, these effects were the result of the hepatomegaly induced by ethanol and were also observed in sham-operated animals fed the diets containing ethanol. An apparent decrease in percent restitution of live weight was observed at 24 hr after hepatectomy in the ethanol-fed animals. However, this was caused by a marked increase in hepatocyte size in the controls, which matched the already enlarged hepatocytes in the ethanol-fed animals. Partial hepatectomy was found to transiently increase the lipid content of the livers in control animals. In ethanol-fed animals partial hepatectomy resulted in markedly fatty livers, as observed both histologically and chemically, which exceeded these abnormalities in alcohol-fed sham-operated rats. In conclusion, long-term ethanol consumption prior to partial hepatectomy and continuous ethanol consumption after the operation did not affect negatively the complete restitution of the liver when compared with controls.

Animals↗