Metabolism of ethanol

Ethanol is consumed widely. Microbial fermentation in the large intestine of humans can produce about 3 g of ethanol per day. Ethanol is rapidly absorbed throughout the gastrointestinal tract or, when inhaled, through the lungs. It is metabolized in the liver by a process having zero-order kinetics i.e., the rate of oxidation is constant with time. The amount metabolized per unit time depends on 

Ethanol oxidation begins with conversion to acetaldehyde by alcohol dehydrogenase (M.W. 85,000), a zinc-containing, NAD+-dependent enzyme that is a relatively nonspecific cytoplasmic enzyme with a of about 1 mM/L  

Acetaldehyde is rapidly converted to acetate by NAD+-dependent aldehyde dehydrogenase  

Ethanol is also oxidized by the mixed-function oxidase of smooth endoplasmic reticulum, which requires NADPH, oxygen, and a cytochrome P-450 electron transport system (Chapter 14)  

Many drugs are metabolized by this enzyme, hence the competition between ethanol and other drugs (e.g.. 

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The microsomal ethanol oxidizing system is another mechanism of ethanol metabolism. CYP2E1 may be an important enzyme in the metabolism of ethanol in heavy drinkers, who may have a 10-fold increase in activity. Two aUehc variants in the gene cl and c2) are associated with differing enzymatic activity. Approximately 40% of Japanese have the more active c2 allele, which is rare in individuals of European heritage (Sun et al. 2002). It is not believed to be a risk or protective factor in the development of alcohohsm, although current studies are examining its relationship to a variety of ethanol-related diseases. 

Alcohol abuse is a major clinical problem in many countries and has been the subject of investigation for many years by those interested in determining the molecular basis of ethanol-induced liver dam e (see Lieber, 1990). These intensive and extended efforts have revealed much about the metabolism of ethanol in the liver and about the toxicity of its primary oxidative product, acetaldehyde. They have not, however, folly elucidated the molecular mechanisms that lead to the typical features of alcoholic liver injury steatosis, necrosis and eventually cirrhosis. 

Albano, E., Tomasi, A., Goria-Gatti, L. and Dianzani, M.U. (1988). Spin trapping of free radical species produced during the microsomal metabolism of ethanol. Chem. Biol. Interact. 65, 223-234. 

Hepatic metabolism of ethanol involves a nonlinear saturable pathway. Young children have a limited ability to metabolize and thereby detoxify ethanol. Ethanol intoxication has been recorded in children with blood levels as low as 25 mg/dL. Alcohol has a volume of distribution of approximately 0.65 L/kg. Ingestion of 20 mL of a 10% alcohol solution will produce a blood level of 25 mg/dL in a 30 pound child. The American Academy of Pediatrics (AAP) Committee on Drugs recommends that pharmaceutical formulations intended for use in children should not produce ethanol blood levels of >25 mg/dL after a single dose. 

After oral ingestion, ethanol pharmacokinetics must take into account (1) Absorption from the gastrointestinal tract. Since ethanol is absorbed most efficiently from the small intestines, the rate of gastric emptying is an important factor that governs the rate of rise of blood alcohol concentration (BAC), i.e., the slope of the ascending limb of the BAC-time curve, and the extent of first pass metabolism of ethanol by the liver and stomach. (2) Distribution of ethanol in the body. Ethanol distributes equally in total body water, which is related to the lean body mass of the person, and (3) the elimination of ethanol from the body, which occurs primarily by metabolism in the liver, first to acetaldehyde and then to acetate [7]. 

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. 

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. 

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. 

Some metabolism of ethanol by ADH occurs in the stomach in men, but a smaller amount occurs in women, who appear to have lower levels of the gastric enzyme. This difference in gastric metabolism of alcohol in women probably contributes to the sex-related differences in blood alcohol concentrations noted above. 

This enzyme system, also known as the mixed function oxidase system, uses NADPH as a cofactor in the metabolism of ethanol (Figure 23-1, right) and consists primarily of cytochrome P450 2E1, 1A2, and 3A4 (see Chapter 4). 

At blood concentrations below 100 mg/dL (22 mmol/L), the MEOS system, which has a relatively high Km for alcohol, contributes little to the metabolism of ethanol. However, when large amounts of ethanol are consumed, the alcohol dehydrogenase system becomes saturated owing to depletion of the required cofactor, NAD+. As the concentration of... 

H2 antagonists compete with creatinine and certain drugs (eg, procainamide) for renal tubular secretion. All of these agents except famotidine inhibit gastric first-pass metabolism of ethanol, especially in women. Although the importance of this is debated, increased bioavailability of ethanol could lead to increased blood ethanol levels. 

We have already discussed a therapeutic application of inhibition in the example of ethanol being used as an antidote to ethylene glycol or methanol poisoning. There are many other such cases which could also be cited. Antabuse , disulfiram, prevents the metabolism of ethanol. As a result a person under treatment with Antabuse will become violently ill if s/he consumes ethanol. Barbiturates are rapidly metabolized especially if a person has been on a prescription for some time. Administering the antibacterial chloramphenicol will inhibit the breakdown of barbiturates and in so doing prolong their sedative action. 

Acetaldehyde is a natural product of combustion and photo-oxidation of hydrocarbons commonly found in the atmosphere. It is an important industrial chemical and may be released into the air or in wastewater during its production and use. It has been detected at low levels in drinking-water, surface water, rainwater, effluents, engine exhaust and ambient and indoor air samples. It is also photochemically produced in surface water. Acetaldehyde is an intermediate product in the metabolism of ethanol and sugars and therefore occurs in trace quantities in human blood. It is present in small amounts in all alcoholic beverages, such as beer, wine and spirits and in plant juices and essential oils, roasted coffee and tobacco smoke (lira et al., 1985 Hagemeyer, 1991 United States National Library of Medicine, 1998). 

Obe, G, Jonas, R. Schmidt, S. (1986) Metabolism of ethanol in vitro produces a compound... 

The metabolism of ethanol results in a massive increase in the concentration I of cytosolic NADH in the liver. 

A. Normal gluconeogenesis in the absence of ethanol consumption. B. Inhibition of gluconeogenesis resulting from hepatic metabolism of ethanol. 

The consumption and subsequent metabolism of ethanol inhibits gluconeogenesis, leading to hypoglycemia in individuals with depleted stores of glycogen. Alcohol consumption can also increase the risk for hypoglycemia in patients using insulin. 

Ethanol. As with morphine addiction, tolerance to alcohol is developed, and a lack of ethanol produces withdrawal symptoms. Tire principal route of metabolism of ethanol (both ingested and the small amount of endogenous alcohol) is believed to be oxidation in the liver to the chemically reactive acetaldehyde (p. 774),874/875 which is further oxidized to acetate. Some theories of alcoholism assume that addiction, and possibly also the euphoric feeling experienced by some drinkers, results from a metabolite of ethanol in the brain. For example, acetaldehyde could form alkaloids (Eq. 30-5).876... 

The rate-limiting factor in the metabolism of ethanol is the availability of NAD. ... 

Normalization of GSH stable state levels in mitochondria opposes the oxidative stress induced by oxidative metabolism of ethanol. 

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