Metabolic alterations produced in the liver by chronic ethanol administration. Changes related to energetic parameters of the cell.
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ABSTRACT:
SUBMITTER: Bernstein J
PROVIDER: S-EPMC1177838 | biostudies-other | 1973 Jun
REPOSITORIES: biostudies-other
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Project description:1. Administration of ethanol (14g/day per kg) for 21-26 days to rats increases the ability of the animals to metabolize ethanol, without concomitant changes in the activities of liver alcohol dehydrogenase or catalase. 2. Liver slices from rats chronically treated with ethanol showed a significant increase (40-60%) in the rate of O(2) consumption over that of slices from control animals. The effect of uncoupling agents such as dinitrophenol and arsenate was completely lost after chronic treatment with ethanol. 3. Isolated mitochondria prepared from animals chronically treated with ethanol showed no changes in state 3 or state 4 respiration, ADP/O ratio, respiratory control ratio or in the dinitrophenol effect when succinate was used as substrate. With beta-hydroxybutyrate as substrate a small but statistically significant decrease was found in the ADP/O ratio but not in the other parameters or in the dinitrophenol effect. Further, no changes in mitochondrial Mg(2+)-activated adenosine triphosphatase, dinitrophenol-activated adenosine triphosphatase or in the dinitrophenol-activated adenosine triphosphatase/Mg(2+)-activated adenosine triphosphatase ratio were found as a result of the chronic ethanol treatment. 4. Liver microsomal NADPH oxidase activity, a H(2)O(2)-producing system, was increased by 80-100% by chronic ethanol treatment. Oxidation of formate to CO(2)in vivo was also increased in these animals. The increase in formate metabolism could theoretically be accounted for by an increased production of H(2)O(2) by the NADPH oxidase system plus formate peroxidation by catalase. However, an increased production of H(2)O(2) and oxidation of ethanol by the catalase system could not account for more than 10-20% of the increased ethanol metabolism in the animals chronically treated with ethanol. 5. Results presented indicate that chronic ethanol ingestion results in a faster mitochondrial O(2) consumption in situ suggesting a faster NADH reoxidation. Although only a minor change in mitochondrial coupling was observed with isolated mitochondria, the possibility of an uncoupling in the intact cell cannot be completely discarded. Regardless of the mechanism, these changes could lead to an increased metabolism of ethanol and of other endogenous substrates.
| S-EPMC1177837 | biostudies-other
Project description:1. Liver slices from rats treated with thyroxine show an increased rate of O(2) consumption. The extra consumption, but not the basal respiration, can be abolished by ouabain. 2. Dinitrophenol is not effective in increasing the rate of O(2) consumption of liver slices from thyroxine-treated animals but its effectiveness can be recovered in the presence of ouabain. 3. (Na(+)+K(+))-stimulated adenosine triphosphatase activity of liver was increased by administration of thyroxine in vivo. No changes were found in total Mg(2+)-stimulated adenosine triphosphatase activity. 4. Mitochondrial alpha-glycerophosphate dehydrogenase and microsomal NADPH oxidase activity were increased by both thyroxine and chronic ethanol treatment. 5. Liver slices from animals chronically treated with ethanol synthesize urea at an increased rate. 6. Mitochondrial size (section area) is markedly increased in the liver of animals chronically treated with ethanol. 7. Acute administration of ethanol in doses of 4 and 6g/kg significantly increases the uptake of (131)I-labelled thyroxine by the liver. 8. Work reported here, along with results from other investigators, indicates marked similarities between the effects produced in the liver by chronic administration of ethanol and by thyroid hormones.
| S-EPMC1177839 | biostudies-other
Project description:1. 2,4-Dinitrophenol (0.1mm) increases by 100-160% the rate of ethanol metabolism by rat liver slices incubated in a medium saturated with a gas mixture containing O(2)+CO(2)+N(2) (18:5:77). Similar effects are produced by relatively low concentrations of arsenate (10mm). At higher concentrations (37.5 and 50mm) arsenate inhibits the rate of ethanol metabolism. 2. When liver slices are incubated under an atmosphere containing O(2)+CO(2) (95:5) the metabolism of ethanol increases by about 100% over that obtained with O(2)+CO(2)+N(2) (18:5:77). However, under these conditions the activating effect of dinitrophenol is no longer observed. 3. Chronic administration of ethanol to rats for 3-4 weeks, in doses from 3 to 8g/kg per day, increases by 70-90% the ability of the liver to metabolize ethanol. In the liver slices of these rats, although an O(2)+CO(2)+N(2) (18:5:77) mixture was used, dinitrophenol does not further increase the metabolism of ethanol. If the chronic administration of ethanol is discontinued for two weeks, the rate of ethanol metabolism is lowered to control values and the activating effect of dinitrophenol is recovered. 4. No change in alcohol dehydrogenase activity was found in the liver of the rats in which the metabolism of ethanol had been increased as a result of the chronic ethanol treatment; a 40% increase in the activity of succinate dehydrogenase was observed.
| S-EPMC1179114 | biostudies-other
Project description:Imatinib is a highly effective drug in up-front treatment of chronic myeloid leukemia (CML). In children impaired longitudinal growth has been reported as side effect exerted by this drug under prolonged therapy. We therefore prospectively evaluated alterations of bone biochemical markers in pediatric patients with CML under ongoing imatinib exposure.Bone metabolic markers (calcium, phosphate, magnesium, parathyroid hormone, vitamin D, procollagen type l N propeptide [PINP], and C-terminal cross-linking telopeptide of collagen [CTX-I], osteocalcin [OC]; pyridinoline [PYD], and desoxypyridinoline [DPD]) were determined in 17 patients with CML aged 4-17 years under imatinib treatment in three-month intervals over a 2.5 year period.Hyperparathyroidism developed in 8/17 patients and low 25-hydroxyvitamin-D3 levels were found in 15/17 patients. Increased OC levels were detected in 58% of all specimen showing a linear significant decline of -0.30 µg OC per l per week (p=0.04). Serum PINP was lowered in 25% and serum CTX-I was above the normal range in 57% of the specimen originating exclusively from prepupertal patients. Urine PYD and Urine DPD levels were above the normal range in 10% and 9%, respectively, of all specimen collected and a statistically significant linear decline of -0.16 nmol DPD/mg creatinine/week was calculated (p=0.01).Bone remodeling may be dysregulated by imatinib. Data suggest that impaired bone formation exceeds that of decreased bone resorption. Regular evaluation of the skeletal actions during long-term imatinib treatment in childhood CML is warranted.
| S-EPMC3560809 | biostudies-literature
Project description:Alcoholics have alterations in endocrine and immune functions and increased susceptibility to stress-related disorders. A longitudinal analysis of chronic ethanol intake on homeostatic mechanisms is, however, incompletely characterized in primates.Plasma proteins (n = 60; Luminex) and hormones (adrenocorticotropic hormone [ACTH]; cortisol) were repeatedly measured in adult male cynomolgus monkeys (Macaca fascicularis, n = 10) during a 32-month experimental protocol at baseline, during induction of water and ethanol (4% w/v in water) self-administration, after 4 months, and after 12 months of 22-hour daily concurrent access to ethanol and water.Significant changes were observed in ACTH, cortisol, and 45/60 plasma proteins: a majority (28/45) were suppressed as a function of ethanol self-administration, 8 proteins were elevated, and 9 showed biphasic changes. Cortisol and ACTH were greatest during induction, and correlations between these hormones and plasma proteins varied across the experiment. Pathway analyses implicated nuclear factor ?-light-chain-enhancer of activated B cells (NF-?B) and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) as possible mediators of ethanol-induced effects on immune-related proteins in primates.Chronic ethanol consumption in primates leads to an allostatic state of physiological compromise with respect to circulating immune- and stress-related proteins in NF-?B- and STAT/JAK-related pathways in correlation with altered endocrine activity.
| S-EPMC3324628 | biostudies-other
Project description:Chronic exposure to opioids induces adaptations in brain function that lead to the formation of the behavioral and physiological symptoms of drug dependence and addiction. Genome wide analysis of molecular effects of protracted morphine or saccharin intake in C57BL/6J mice over a period of 7 months provides an opportunity to observe the alterations in the brain that accompany long-term drug addiction.
2016-05-01 | GSE78280 | GEO
Project description:Chronic ethanol consumption is a risk factor for colorectal cancer, and ethanol-induced reactive oxygen species have been suggested to play important roles in the pathogenesis of ethanol-related colorectal cancer (ER-CRC). In this study, the effects of 10-week chronic administration of ethanol on the colonic levels of oxidative stress and advance glycation end product (AGE) levels, as well as fecal microbiota structures, were examined in a mouse model. Chronic oral administration of ethanol in mice (1.0 mL of 1.5% or 5.0% ethanol (v/v) per day per mouse, up to 10 weeks) resulted in the elevation of colonic levels of oxidative stress markers (such as 8-hydroxy-2'-deoxyguanosine and 4-hydroxynonenal) compared to control mice, and this was consistently accompanied by elevated levels of inflammation-associated cytokines and immune cells (Th17 and macrophages) and a decreased level of regulatory T (Treg) cells to produce colonic lesions. It also resulted in an alteration of mouse fecal microbiota structures, reminiscent of the alterations observed in human inflammatory bowel disease, and this appeared to be consistent with the proposed sustained generation of oxidative stress in the colonic environment during chronic ethanol consumption. Moreover, the first experimental evidence that chronic ethanol administration results in elevated levels of advanced glycation end products (AGEs) and their receptors (RAGE) in the colonic tissues in mice is also shown, implying enhanced RAGE-mediated signaling with chronic ethanol administration. The RAGE-mediated signaling pathway has thus far been implicated as a link between the accumulation of AGEs and the development of many types of chronic colitis and cancers. Thus, enhancement of this pathway likely exacerbates the ethanol-induced inflammatory states of colonic tissues and might at least partly contribute to the pathogenesis of ER-CRC.
| S-EPMC7880462 | biostudies-literature
Project description:Administration of ethanol as part of a nutritionally adequate liquid diet to female Wistar rats was found to depress markedly incorporation of labelled glucose into adipose-tissue acylglycerol fatty acids. Similar results with labelled pyruvate and acetate suggested inhibition of the fatty-acid-synthesis pathway at, or distal to, the acetyl-CoA carboxylase step. Activities of acetyl-CoA carboxylase and fatty acid synthetase were markedly lower in ethanol-fed animals. The activity of another lipogenic enzyme, phosphatidate phosphohydrolase, was not affected by chronic ethanol feeding. These findings suggest that chronic ethanol administration has marked effects on adipose-tissue lipogenesis.
| S-EPMC1149035 | biostudies-other
Project description:BackgroundWe have previously reported that chronic treatment with certain 'beta-blockers' reduces airway hyperresponsiveness (AHR) to methacholine in a murine model of asthma.MethodsAirway resistance was measured using the forced oscillation technique in ovalbulmin-sensitized and ovalbulmin-challenged mice treated with several beta-adrenoceptor (beta-AR) ligands. We used the selective beta 2-AR ligand ICI 118,551 and the preferential beta 1-AR ligand metoprolol to investigate the receptor subtype mediating the beneficial effect. Expression of beta-ARs was evaluated using immunofluorescence. We evaluated several signaling proteins by western blot using lung homogenates, and measured the relaxation of the isolated trachea produced by EP2 and IP receptor agonists.ResultsFour findings were associated with the decreased AHR after chronic beta-blocker treatment: (1) the highly selective beta 2-AR antagonist/inverse agonist, ICI 118,551 produced the bronchoprotective effect; (2) beta 2-AR up-regulation resulted from chronic 'beta-blocker' treatment; (3) reduced expression of certain proteins involved in regulating bronchial tone, namely, Gi, phosphodiesterase 4D and phospholipase C-beta 1; and (4) an enhanced bronchodilatory response to prostanoid agonists for the IP and EP2 receptors.ConclusionsThese data suggest that in the murine model of asthma, several compensatory changes associated with either increased bronchodilator signaling or decreased bronchoconstrictive signaling, result from the chronic administration of certain 'beta-blockers'.
| S-EPMC2775056 | biostudies-literature
Project description:Most ingested ethanol is metabolized in the liver to acetaldehyde and then to acetate, which can be oxidized by the brain. This project assessed whether chronic exposure to alcohol can increase cerebral oxidation of acetate. Through metabolism, acetate may contribute to long-term adaptation to drinking. Two groups of adult male Sprague-Dawley rats were studied, one treated with ethanol vapor and the other given room air. After 3 weeks the rats received an intravenous infusion of [2-(13) C]ethanol via a lateral tail vein for 2 h. As the liver converts ethanol to [2-(13) C]acetate, some of the acetate enters the brain. Through oxidation the (13) C is incorporated into the metabolic intermediate ?-ketoglutarate, which is converted to glutamate (Glu), glutamine (Gln), and GABA. These were observed by magnetic resonance spectroscopy and found to be (13) C-labeled primarily through the consumption of ethanol-derived acetate. Brain Gln, Glu, and, GABA (13) C enrichments, normalized to (13) C-acetate enrichments in the plasma, were higher in the chronically treated rats than in the ethanol-naïve rats, suggesting increased cerebral uptake and oxidation of circulating acetate. Chronic ethanol exposure increased incorporation of systemically derived acetate into brain Gln, Glu, and GABA, key neurochemicals linked to brain energy metabolism and neurotransmission. The liver converts ethanol to acetate, which may contribute to long-term adaptation to drinking. Astroglia oxidize acetate and generate neurochemicals, while neurons and glia may also oxidize ethanol. When (13) C-ethanol is administered intravenously, (13) C-glutamine, glutamate, and GABA, normalized to (13) C-acetate, were higher in chronic ethanol-exposed rats than in control rats, suggesting that ethanol exposure increases cerebral oxidation of circulating acetate.
| S-EPMC6145094 | biostudies-literature