The time-course of the effects of ethanol on the redox and phosphorylation states of rat liver (original) (raw)
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The redox-state in relation to ethanol metabolism by rat and guinea pig liver in vitro
Archives of Biochemistry and Biophysics, 1972
Effect of hepatic redox-state on the rate of ethanol metabolism and citric acid cycle activity has been studied in rat and guinea pig liver. Cytoplasmic (NADH)/ (NAD>l ratio in guinea pig liver is about &fold higher than in rat liver. Although, hepatic alcohol dehydrogenase (EC 1.1.1.1) activity is similar in the two species, ethanol metabolism by rat liver in vitro, is about 3 times greater than by guinea pig liver. Addition of ethanol results in a a-fold increase in the hepatic redox-state in the rat but, causes a small increase in the guinea pig. Ethanol-induced increase in hepatic (NADH)/(NAD) ratio, results in a 49-60y0 inhibition of 14COz formation from various radioactive substrates in the rat. However, in guinea pig liver where this ratio is high, W02 formation is already lower by 39-50% than in rat liver and et,hanol addition does not result in a further decrease. The inhibitory effect of ethanol on 'CO2 formation is also observed in rat kidney cortex slices. However, this effect can be abolished by the addition of methylene blue or pyrasole. This study shows that in normal liver cytoplasmic redox-state regulates the rate of ethanol metabolism and that the activity of hepatic alcohol dehydrogenase is not a rate-limiting factor. Furthermore, the inhibitory effect of ethanol on COZ production and therefore on citric acid cycle activity is a consequence of increased (NADH)/(NAD) ratio in liver.
Dependence on dose of the acute effects of ethanol on liver metabolism in vivo
Journal of Clinical Investigation, 1975
A B S T R A C T The dose dependence of the acute effects of ethanol upon liver intermediary metabolism in vivo has been demonstrated in rats. Ethanol was given i.p. in doses of 0.69, 1.7, and 3.0 g/kg in equal volumes (20 ml/kg). The liver was freeze-clamped 120 min after injection, and multiple metabolites were measured in the perchloric acid extract of the tissue. Each group showed a significantly different pattern of metabolites, redox states, and phosphorylation potentials although the rate of ethanol disappearance, at least between the two highest dose groups, was not significantly different. The mitochondrial free [NAD+]/[NADH] ratios and the cytoplasmic free [NADP+]/ [NADPH] ratio were paradoxically most reduced with the lowest dose of ethanol and became progressively more oxidized with increasing dose. Once established, the differences in these ratios between the groups tended to persist with time, relatively independent of the concentration of ethanol. In a somewhat different pattern, the phosphorylation potential ([ATP]/[ADP][P.]) remained at the control level in the low-dose group but was significantly elevated in the two higher-dose groups.
FEBS letters, 2000
The efficiency of oxidative phosphorylation was compared between rats chronically fed with ethanol and controls. (i) Results showed that the liver mitochondria state 4 respiratory rate was strongly inhibited, while the corresponding protonmotive force was not affected; (ii) the cytochrome oxidase content and activity were decreased and (iii) the oxidativephosphorylation yield was increased in the ethanol exposed group. Furthermore, oxidative phosphorylation at coupling site II was not affected by ethanol. Cytochrome oxidase inhibition by sodium-azide mimicked the effects of ethanol intoxication in control mitochondria. This indicates that the decrease in cytochrome oxidase activity induced by ethanol intoxication directly increases the efficiency of oxidative phosphorylation.
Archives of Biochemistry and Biophysics, 1998
The effect of chronic ethanol consumption on hepatic Previous studies (Ivester et al., Arch. Biochem. Bio-energy state is complex. Recent studies have demonphys. 322, 14-21, 1995) have established that periportal strated that ATP concentrations, phosphorylation poand perivenous hepatocytes isolated from ethanol-fed tential, and energy charge in liver or hepatocytes from rats demonstrate lower ATP concentrations than ethanol-fed rats are normal if the preparations are adethose in control preparations when the cells are mainquately oxygenated (1, 2). In contrast, if the tissue or tained at very low oxygen tension. In the present inveshepatocytes are allowed to become anoxic, the energy tigation, experiments were implemented with periporstate decreases to significantly lower values in preparatal and perivenous hepatocytes to determine the eftions from ethanol-fed rats as compared with control fects of chronic ethanol consumption on cellular animals (1, 2). This latter observation is consistent respiratory and glycolytic activities, since both conwith earlier reports of ethanol-related decreases in hetribute to maintenance of the energy state of the liver patic energy state measured in tissues allowed to go cell. Both periportal and perivenous hepatocytes from anaerobic before being freeze-clamped for adenine nuethanol-fed rats demonstrated significantly increased, cleotide analyses (3-6). This ethanol-related effect on rather than decreased, respiratory activity when monhepatic energy state has also been observed in intact itored with oxygen concentrations ranging from 16 to animals. French and co-workers (7), using in vivo NMR 140 mM. Whole liver hepatocytes from control and ethspectroscopy, demonstrated more dramatic decreases anol-fed animals demonstrated equivalent oxygen utiin hepatic ATP in ethanol-fed rats than in controls lization, however. Glycolytic activity, monitored by when the animals were subjected to a hypoxic episode. lactate / pyruvate concentrations obtained after both These studies emphasize the increased sensitivity of anaerobic and aerobic incubation protocols, was decreased in both cell types from ethanol-fed animals. liver energy state to oxygen tension in animals sub-The glycogen concentrations in freshly isolated perijected to chronic ethanol administration. portal and perivenous hepatocytes were also de-1 This project was supported by Grant 02887 from the National Since chronic consumption damages hepatic mito-Institute on Alcohol Abuse and Alcoholism. C.G.V.H. was supported chondria such that there are depressions in the rates by NIAAA Training Grant 07565. of electron transport activity (8, 9) and of ATP synthe-2 To whom correspondence should be addressed at Wake Forest sis (10), measurements of oxygen utilization in soni
Chronic low dose ethanol intake: Biochemical characterization of liver mitochondria in rats
Life Sciences, 2000
Liver mitochondria were isolated from male rats exposed for 2 months to low doses of ethanol (3% v/v in drinking water), a condition not associated with tolerance or dependence. The results show no significant changes in the content of reduced or oxidized glutathione in the liver mitochondria of ethanol treated rats with respect to controls. However, a slight but significant increase in lipid peroxidation, accompanied by an increased content of oxidized proteins, was found in el.hanol exposed animals. Mitochondrial content of cytochrome complexes was not significantly affected by ethanol intake. The specific enzymatic activity of cytochrome oxidase showed, however, a . significant decrease in ethanol-treated rats. The slight mitochondrial alterations found in the liver of rats exposed chronically to low doses of ethanol might represent the beginning of a more extensive damage previously observed in rats exposed to high doses of this substance.
Biochemical Pharmacology, 1978
Incorporation in vitro of labeled leucine into isolated rat liver mitochondria was decreased in animals chronically fed ethanol. To avoid artifactual leucine incorporation, no trichloroacetic acid (TCA) precipitation was performed. Further, it was found that when these mitochondrial proteins were separated on sodium dodecyl sulfate polyacrylamide gels, no specific reduction of leucine incorporation into any indi~dua1 protein bands could be detected. This probably reflected a general decrease in amino acid incorporation occurring in these isolated mitochondria. Incorporation in uiuo of labeled arginine detected a decrease in the viability of rat liver mitochondria from chronic ethanol-fed rats. This incorporation revealed a 2&y decrease in the half-life of liver mitochondria from chronic ethanolfed rats. It was also found that arginine incorporation by the cytoplasmic protein-synthesizing system is increased in uivo after chronic ethanol feeding. The results from these experiments suggest that if this reaction were to persist through continuous consumption of ethanol, there would in time be diminished amounts of properly assembled proteins which are necessary for membrane structure and function. Whether or not such induced deficiencies in the mitochondria over a long period of time
Influence of Ethanol on the Liver Metabolism of Fed and Starved Rats
The Biochemical journal, 1965
1. The influence of ethanol on the metabolism of livers from fed and starved rats has been studied in liver-perfusion experiments. Results have been obtained on oxygen consumption and carbon dioxide production, on glucose release and uptake by the liver and on changes in the concentrations of lactate and pyruvate and of beta-hydroxybutyrate and acetoacetate in the perfusion medium. 2. Oxygen consumption and carbon dioxide production were lower in livers from starved rats than in livers from fed rats. Ethanol had no effect on the oxygen consumption of either type of liver. After the addition of ethanol to the perfusion medium carbon dioxide production ceased almost completely, the change being faster in livers from starved rats. 3. With livers from fed rats glucose was released from the liver into the perfusion medium. This release was slightly greater when ethanol was present. With livers from starved rats no release of glucose was observed, and when ethanol was added a marked uptak...
Archives of Biochemistry and Biophysics, 1981
The metabolism of xylitol was studied in the absence or presence of ethanol in cells from 24-h-starved rats, either untreated, Ts treated, or ethanol induced. The relative yields of tritium in water, glucose, and lactate were determined. A simple metabolic model is proposed, from which the specific radioactivity of cytosolic NADH, flux through lactate dehydrogenase, and the relative yield of tritium in water and glucose can be calculated. The model assumes one cytosolic NAD pool and metabolic and isotopic steady state. The measured incorporation of tritium into glucose indicate that the 4A-and 4Bhydrogens of NADH are not fully equilibrated.