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Liver Diseases
Published in George Feuer, Felix A. de la Iglesia, Molecular Biochemistry of Human Disease, 2020
George Feuer, Felix A. de la Iglesia
When ethanol is given with lipid-containing diets, there is increased accumulation of lipids in the liver from dietary fatty acids. When ethanol is consumed with low-fat diets, endogenously synthesized fatty acids accumulate in hepatocytes.357 Some of these actions are connected with the metabolism of ethanol. Ethanol actually competes with fatty acids as normal fuel for hepatic mitochondria. This results in a decreased fatty acid oxidation, and fatty acids derived from adipose tissue depots also accumulate in hepatocytes when the ethanol concentration is high in the cells. In this initial stage, the transport mechanism that eliminates lipids into the blood stream is through the release of lipoproteins and is activated by ethanol. In addition to the functional changes, chronic alcoholism causes more persistent damage to mitochondria, associated with functional abnormalities as reflected in reduced fatty acid oxidation. In short-term human investigations, ethanol intake produced a fall in the level of circulating free fatty acids by affecting fat release from adipose tissue.284 Moreover, free fatty acid turnover was reduced and circulating glycerol decreased.161 The effect of ethanol on the mobilization of free fatty acids is mediated by acetate which is actually the end-product of ethanol metabolism in the liver.568 With progression of the liver injury, lipoprotein secretion falls below normal levels, and this altered lipoprotein secretion aggravates liver damage even further.
Alcohol-Induced Hepatotoxicity
Published in Robert G. Meeks, Steadman D. Harrison, Richard J. Bull, Hepatotoxicology, 2020
All known oxidative pathways of ethanol metabolism result in the production of acetaldehyde. Its metabolism and general effects have been reviewed elsewhere (Lieber, 1982, 1988d). Acetaldehyde is converted to acetate by acetaldehyde dehydrogenase, an enzyme with an interesting polymorphism and associated striking consequences in terms of ethanol intolerance and flushing, exhibited by subjects who harbor an inactive aldehyde dehydrogenase variant (Harada et al., 1980; Yoshida et al., 1984). These aspects will not be discussed in detail here; we shall focus instead on aspects of the toxicity of acetaldehyde most conspicuously related to liver injury.
Characteristics and Theories Related to Acute and Chronic Tolerance Development
Published in S.J. Mulé, Henry Brill, Chemical and Biological Aspects of Drug Dependence, 2019
The biochemical basis of the augmentation of ethanol metabolism is not totally clear. First of all, there is uncertainty as to the rate limiting factor in ethanol metabolism; both limited alcohol dehydrogenase and a limited rate of reoxidation of reduced nicotinamide adenine dinucleotide phosphate108,347 (formed during alcohol oxidation) have been suggested. Secondly, some authors have associated ethanol tolerance with increased activity of hepatic enzymes (alcohol dehydrogenase, catalase, microsomal oxidases) while others have denied a cause-effect relationship. (See reviews210,244,347,348 for details and critical analyses.) Finally, it must be recognized that a number of factors influence the rate of ethanol metabolism in vivo and in vitro, and that in vitro experiments are subject to the introduction of artifacts and may not be representative of what is occurring in the intact organism.
Melatonin modulates oxidative phosphorylation, hepatic and kidney autophagy-caused subclinical endotoxemia and acute ethanol-induced oxidative stress
Published in Chronobiology International, 2020
Natalia Kurhaluk, Halyna Tkachenko, Oleksandr Lukash
The current study demonstrated a different course of ethanol-induced toxicity, subclinical endotoxemia caused by LPS-induced inflammation, and effects of Mel treatment in kidney and liver, as these organs are the principal sites of ethanol metabolism. The liver is the primary organ responsible for the oxidation of ethanol. On the other hand, the kidney is involved in ethanol metabolism as well. The data of the current study revealed that ethanol enhanced fatty acid oxidation in kidney microsomes and peroxisomes and affected activities of some kidney lysosomal hydrolases. Currently, there are no conclusive published data that defines the relationship between oxygen consumption, activities of lysosomal enzymes, and antioxidant defenses in these organs exposed to ethanol, subclinical LPS-induced endotoxemia, and Mel treatment.
Ethanol and its metabolites: update on toxicity, benefits, and focus on immunomodulatory effects
Published in Drug Metabolism Reviews, 2019
Brendan Le Daré, Vincent Lagente, Thomas Gicquel
The acetaldehyde generated by these metabolic pathways is then oxidized by aldehyde dehydrogenase (ALDH) to form acetate. In humans, the ALDH superfamily of NAD+-dependent enzymes is encoded by 16 genes. The cytosolic ALDH1 and mitochondrial ALDH2 isoenzymes are those primarily involved in ethanol metabolism (Vasiliou and Pappa 2000). In contrast to ADH, polymorphisms appear to have a greater influence on ALDH activity. The ALDH2*1 allele (known to code for a highly active variant) is considered to protect against liver disease in alcoholism, whereas the enzyme encoded by ALDH2*2 allele is an inactive enzyme (Cederbaum 2012). Furthermore, chronic ethanol consumption lowers ALDH and increases the acetaldehyde level (Lin et al. 1984). Acetate is not the final metabolite in this pathway because it be converted into CO2, fatty acids, ketones, cholesterol or steroids (Cederbaum 2012).
Orally administered zingerone does not mitigate alcohol-induced hepatic oxidative stress in growing Sprague Dawley rat pups
Published in Drug and Chemical Toxicology, 2023
Bernice Asiedu, Busisani Wiseman Lembede, Trevor Tapiwa Nyakudya, Eliton Chivandi
Nutrition and hepatic pathology affect liver mass; an increase in liver mass can result from a fatty liver, while a decrease can be due to undernutrition (Pandit and Gupta 2019). Since the liver is the center of ethanol metabolism, we examined its gross morphometry and possible oxidative damage. The absolute liver mass and its mass relative to the tibiae length regardless of treatment or sex were unaffected. This agreed with our earlier speculation that NAE and zingerone did not affect the nutritional intake of the rat pups. Malnutrition results in hypoleptinemia (Paillaud et al. 2022). However, leptin was also not affected by any of the treatment interventions.