Ethanol metabolism, alcohol dehydrogenase

Each of the enzyme activities involved in ethanol metabolism (alcohol dehydrogenase, acetaldehyde dehydrogenase, and CYP2E1) exist as a family of isoenzymes. Individual variations in the quantity of these isoenzymes influence a number of factors, such as the rate of ethanol clearance from the blood, the degree of inebriation exhibited by an individual, and differences in individual susceptibihty to the development of alcohol-induced liver disease. 

Metabolism of ethanol by alcohol dehydrogenase and the microsomal ethanol-oxidizing system (MEOS). Alcohol dehydrogenase and aldehyde dehydrogenase are inhibited by fomepizole and disulfiram, respectively. NAD +, nicotinamide adenine dinucleotide NADPH, nicotinamide adenine dinucleotide phosphate. 

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. 

Fermentation is defined as an energy-yielding metabolic pathway that involves no net change in oxidation state. Anaerobic glycolysis is a type of fermentation. The lactic acid fermentation (conversion of glucose to lactate) is important in the manufacture of cheese. Another important fermentation involves cleavage of pyruvate to acetaldehyde and C02, with the acetaldehyde then reduced to ethanol by alcohol dehydrogenase in the reaction that follows ... 

The role of short-chain aliphatic alcohols in the regulation of the respirarory burst is controversial, and several mechanisms may be involved in their effects (Seifert and Schultz 1991). Alcohol metabolism has at least four pathways, the most important one being the oxidation of ethanol by alcohol dehydrogenase. After chronic consumption of ethanol or in the presence of high concentration of ethanol, minor pathways such as the microsomal ethanol oxidising system... 

Many biological processes involve oxidation of alcohols to carbonyl compounds or the reverse process reduction of carbonyl compounds to alcohols Ethanol for example is metabolized m the liver to acetaldehyde Such processes are catalyzed by enzymes the enzyme that catalyzes the oxidation of ethanol is called alcohol dehydrogenase... 

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. 

Ethanol is almost entirely metabolized in the liver. The first step, oxidation by alcohol dehydrogenase, yields acetaldehyde, a reactive and toxic compound. Essentially all of the acetaldehyde is converted to acetate by the liver enzyme aldehyde dehydrogenase. Aldehyde dehydrogenase is inhibited by the drag disulfiram. Given alone, disulfiram is a nontoxic substance. However, ethanol consumption in the presence of... 

Ethanol is oxidized by alcohol dehydrogenase (in the presence of nicotinamide adenine dinucleotide [NAD]) or the microsomal ethanol oxidizing system (MEOS) (in the presence of reduced nicotinamide adenine dinucleotide phosphate [NADPH]). Acetaldehyde, the first product in ethanol oxidation, is metabolized to acetic acid by aldehyde dehydrogenase in the presence of NAD. Acetic acid is broken down through the citric acid cycle to carbon dioxide (CO2) and water (H2O). Impairment of the metabolism of acetaldehyde to acetic acid is the major mechanism of action of disulfiram for the treatment of alcoholism. 

Deltour L, Foglio MH, Deuster G. Metabolic deficiencies in alcohol dehydrogenase Adhl, Adh3, and Adh4 null mutant mice Overlapping roles of Adhl and Adh4 in ethanol clearance and metabolism of retinol to retinoic acid. J Biol Chem 1999 274 16796-16801. 

Since many of the transformations undergone by metabolites involve changes in oxidation state, it is understandable that cofactors have been developed to act as electron acceptors/ donors. One of the most important is that based on NAD/NADP. NAD+ can accept what is essentially two electrons and a proton (a hydride ion) from a substrate such as ethanol in a reaction catalysed by alcohol dehydrogenase, to give the oxidized product, acetaldehyde and the reduced cofactor NADH plus a proton (Figure 5.2). Whereas redox reactions on metal centres usually involve only electron transfers, many oxidation/reduction reactions in intermediary metabolism, as in the case above, involve not only electron transfer but... 

The final reactions to be considered in the metabolism of ethanol in the liver are those involved in reoxidation of cytosolic NADH and in the reduction of NADP. The latter is achieved by the pentose phosphate pathway which has a high capacity in the liver (Chapter 6). The cytosolic NADH is reoxidised mainly by the mitochondrial electron transfer system, which means that substrate shuttles must be used to transport the hydrogen atoms into the mitochondria. The malate/aspartate is the main shuttle involved. Under some conditions, the rate of transfer of hydrogen atoms by the shuttle is less than the rate of NADH generation so that the redox state in the cytosolic compartment of the liver becomes highly reduced and the concentration of NAD severely decreased. This limits the rate of ethanol oxidation by alcohol dehydrogenase. 

F. The electrons that are generated from the first step in ethanol metabolism (catalyzed by alcohol dehydrogenase) are transported into the mitochondrion by these two shuttles. 

This phenomenon of saturation is seen with alcohol (ethanol) which rapidly saturates its first metabolic enzyme, alcohol dehydrogenase, and thereafter is eliminated at a constant rate, which approximates 10 ml per hour. And this is the figure you will find in many textbooks. However, as the Cp... 

Ethanol is metabolized primarily in the liver by at least two enzyme systems. The best-studied and most important enzyme is zinc dependent alcohol dehydrogenase. Salient features of the reaction can be seen in Fig. 35.1. The rate of metabolism catalyzed by alcohol dehydrogenase is generally linear with time except at low ethanol concentrations and is relatively independent of the ethanol concentration (i.e., zero-order kinetics). The rate of metabolism after ingestion of different amounts of ethanol is illustrated in Fig. 35.2. 

In adults, ethanol is metabolized at about 10 to 15 mL/hour. Since metabolism of ethanol is slow, ingestion must be controlled to prevent accumulation and intoxication. There is little evidence that chronic ingestion of ethanol leads to a significant induction of alcohol dehydrogenase, even in heavy drinkers. 

Mechanism of Action An alcohol dehydrogenase inhibitor that inhibits the enzyme that catalyzes the metabolism of ethanol, ethylene glycol, and methanol to their toxic metabolites. Therapeutic Effect Inhibits conversion of ethylene glycol and methanol into toxic metabolites. 

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