Liver ethanol metabolism

As regards toxicity, pyrazole itself induced hyperplasia of the thyroid, hepatomegaly, atrophy of the testis, anemia and bone marrow depression in rats and mice (72E1198). The 4-methyl derivative is well tolerated and may be more useful than pyrazole for pharmacological and metabolic studies of inhibition of ethanol metabolism. It has been shown (79MI40404) that administration of pyrazole or ethanol to rats had only moderate effects on the liver, but combined treatment resulted in severe hepatotoxic effects with liver necrosis. The fact that pyrazole strongly intensified the toxic effects of ethanol is due to inhibition of the enzymes involved in alcohol oxidation (Section 4.04.4.1.1). 

Ethanol metabolism occurs mainly in the liver and proceeds by oxidation in two steps, first to acetaldehyde (CHjCHO) and then to acetic add (CH3CO2H)- When continuously present in the body, ethanol and acetaldehyde are toxic, leading to the devastating physical and metabolic deterioration... 

Alcohol dehydrogenase is a cytoplasmic enzyme mainly found in the liver, but also in the stomach. The enzyme accomplishes the first step of ethanol metabolism, oxidation to acetaldehyde, which is further metabolized by aldehyde dehydrogenase. Quantitatively, the oxidation of ethanol is more or less independent of the blood concentration and constant with time, i.e. it follows zero-order kinetics (pharmacokinetics). On average, a 70-kg person oxidizes about 10 ml of ethanol per hour. 

Iturriage, H., Ugarte, H. and Israel, Y, (1980). Hepatic vein oxygenation, liver blood flow and the rate of ethanol metabolism in recently abstinent alcoholic patients. Eur. J. Clin. Invest. 10, 211-218. 

Liver metabolism is affected by methylxanthines. In high doses, theophylline and caffeine increase the level of cyclic AMP. Very high levels of methylxanthines decrease the level of branched chain and aromatic amino acids in plasma. Coffee appears to have little effect on ethanol metabolism. 

Acetaldehyde is oxidized to acetic acid by NAD+-dependent aldehyde dehydrogenases (ALDH) in liver and nasal mucosal preparations. Its administration to rats causes an increase in urinary excretion of sulfur metabolites and it is known to react with cysteine to produce a thiazolidine 4-carboxylic acid derivative that can be A -nitro-sated in vivo upon co-administration of nitrite (lARC, 1985). Many studies have been published subsequently, but these have been mainly in the context of ethanol metabolism. 

Alcohol-related liver diseases are complex, and ethanol has been shown to interact with a large number of molecular targets. Ethanol can interfere with hepatic lipid metabolism in a number of ways and is known to induce both inflammation and necrosis in the liver. Ethanol increases the formation of superoxide by Kupffer cells thus implicating oxidative stress in ethanol-induced liver disease. Similarly prooxidants (reactive oxygen species) are produced in the hepatocytes by partial reactions in the action of CYP2E1, an ethanol-induced CYP isoform. The formation of protein adducts in the microtubules by acetaldehyde, the metabolic product formed from ethanol by alcohol dehydrogenase, plays a role in the impairment of VLDL secretion associated with ethanol. 

Answer The first step in the synthesis of glucose from lactate in the liver is oxidation of the lactate to pyruvate like the oxidation of ethanol to acetaldehyde, this requires NAD+. Consumption of alcohol forces a competition for NAD+ between ethanol metabolism and gluconeogenesis, reducing the conversion of lactate to glucose and resulting in hypoglycemia. The problem is compounded by strenuous exercise and lack of food because at these times the level of blood glucose is already low. 

Nuutinen HU. Activities of ethanol-metabolizing enzymes in liver diseases. Scand J Gastroenterol 1986 21 678-84. 

Sato A, Nakajima T. 1979. Enhanced activity of liver drug-metabolizing enzymes following chronic ethanol consumption and starvation. Arh Hig Rada Toksikol 30 645-651. 

Ethanol cannot be excreted and must be metabolized, primarily by the liver. This metabolism occurs by two pathways. The first pathway comprises two steps. The first step, catalyzed by the enzyme alcohol dehydrogenase, takes place in the cytoplasm ... 

Lieber, C.S. Hepatic and metabolic effects of ethanol pathogenesis and prevention. Ann. Med. 1994 26 325-330 Ethanol metabolism, cirrhosis and alcoholism. Clin. Chim. Acta 1997 257 59-84 Role of oxidative stress and antioxidant therapy in alcoholic and non-alcoholic liver diseases. Adv. Pharmacol. 1997 38 601-628... 

Horse liver alcohol dehydrogenase, HLADH, (also abbreviated as ADH or LADH) is the most extensively studied oxido-reductase. It plays a central role in ethanol metabolism and has been one of the main tools for understanding the mechanism of this process.15 it was crystaliized from horse liver in 1948 by Bonnichen and Wassen and is commercially available. Three isozymes EE, ES and SS are formed by dimeric combination of two different, E or S (E "ethanol-active" and S "steroid active"), protein chains. 16 The EE- isozyme of HLADH has been used in organic synthesis. 

Normally, 90-98% of the ethanol that enters the body is completely oxidized, predominantly in the liver, eventually entering the citric acid cycle or utilized in anabolic synthetic pathways. The kidney and lungs excrete only 5-10% of an absorbed dose unchanged. The rate of ethanol metabolism varies between individuals, by age, and may be under genetic control. 

Ethanol is readily absorbed following inhalation or oral exposure. In the bloodstream, ethanol is rapidly distributed into total body water. Ethanol is removed from the blood primarily by metabolism in the liver. Ethanol is metabolized to acetaldehyde and later to acetic acid by two major pathways acetaldehyde (ADH) and the ethanol-oxidizing system in the endoplasmic reticulum. 

Poisoning with mushrooms in this group occurs when ethanol is consumed shortly before or within 5 days after eating the mushrooms. Coprine (N(5)-(l-hydroxy cyclopropyl)-L-glutamine) is the active constituent in these mushrooms and has been shown to inhibit liver aldehyde dehydrogenase. The active metabolite, cyclopropanone hydrate, has also been shown to possess similar activity. This inhibition of ethanol metabolism at the point of aldehyde dehydrogenase results in accumulation of acetaldehyde. In the absence of concurrent ethanol consumption, these mushrooms are edible. 

The belief that alcoholics are more susceptible to the toxicity of 2,4-DNP during occupational exposure (Perkins 1919) may indicate an interaction with ethanol (and possibly other alcohols) or it may simply be a function of the compromised physiological state of alcoholics. 2,4-DNP appears to markedly increase the rate of ethanol metabolism in rat liver slices by 100-160% (Videla and Israel 1970) and in rats in vivo by 20-30% (Israel et al. 1970). Because 2,4-DNP uncouples mitochondrial electron transport from oxidative phosphorylation, the oxidation of NADH to NAD is accelerated in the mitochondria. Reoxidation of NADH rather than the activity of alcohol dehydrogenase is the rate-limiting step in the metabolism of ethanol, and, therefore, the metabolic effect of 2,4-DNP enhances the clearance of ethanol (Eriksson et al. 1974). Because 2,4-DNP is known to augment the rate of respiration and perspiration, 2.7-8.2% of the initial dose of ethanol was also eliminated by expiration and cutaneous evaporation in the rat (Israel et al. 1970). 

In animals pretreated with ethanol, metabolism of cocaine to norcocaine and benzoylnorecgonine increased, as reflected by higher tissue AUCs, as compared with those receiving water. Ethanol pretreatment also resulted in measurable levels of norcocaethylene in liver and lung. These observations are consistent with the increased hepatotoxicity (presumably due to enhanced N-oxidative metabolism) observed when mice were exposed to cocaine or cocaethylene and the esterase inhibitor diazinon (Roberts et al. 1992 Thompson et al. 1979). This shift toward N-oxidative metabolism provides a mechanism to explain potentiation of cocaine hepatotoxicity by ethanol (lover et al. 1991). Detection of norcocaethylene in ethanol- pretreated rats is consistent with norcocaethylene detected in the hair of heavy cocaine users, suggesting common pathways including hydrolysis, transesterification, and N-demethylation (figure 1) (Cone etal. 1991). 

The overabundance of NADH also inhibits fatty acid oxidation. The metabolic purpose of fatty acid oxidation Is to generate NADH for ATP generation by oxidative phosphorylation, but an alcohol consumer s NADH needs are met by ethanol metabolism. In fact, the excess NADH signals that conditions are right for fatty acid synthesis. Hence, triacylglyc-erols accumulate in the liver, leading to a condition known as Tatty liver."... 

Because cytosolic enzymes such as aspartate aminotransferase, lipase, and amylase appear in the blood after liver or pancreatic damage, we hypothesized that FAEE synthase, which is both cystolic and membrane bound, is released into the blood of patients with liver or pancreatic disease. We demonstrated that patients with liver or pancreatic disease release FAEE synthase into their plasma in amounts proportional to the level of asparate aminotransferase, amylase, or lipase (Aleryani, 1996). The presence of FAEE synthase in plasma may permit nonoxidative ethanol metabolism in the circulation in such individuals, although this remains to be conclusively demonstrated. 

Although D-fructose stimulates ethanol metabolism in tissues and perfused liver, the use of D-fructose in the treatment of ethanol intoxication in intact animals still remains controversial.234-239... 

The mechanism of hepatocellular damage by alcohol and the reasons why there are marked interindividual variations in the susceptibility to alcohol-related liver damage are poorly understood. Ethanol may be metabolized to acetaldehyde by cytosolic alcohol dehydrogenase or it can be oxidized by the microsomal ethanol oxidase system. The metabolites from ethanol metabolism can have direct toxic effects on the cell or they may lead to a reduction in membrane fluidity or increased free radical damage potentiated by a reduction in hepatic glutathione (L9, LIO, R12). 

Ingested alcohol is metabolized to acetaldehyde mainly by the action of liver alcohol dehydrogenase. Catalase (21,22), the microsomal ethanol oxidizing system (MEOS) (23-25), and extrahepatic pathways have also been considered as ethanol metabolizers, but these systems probably play only a minor role in most cases (for a detailed discussion of ethanol metabolism, see review by Hawkins and Kalant, 26). Ethanol metabolism produce an increase in the NADH/NAD+ ratio in the liver... 

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