Acetaldehyde, ethanol metabolism

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. 

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. 

During the biological aging of sherry, the concentration of ethanol decreases because of its consumption by flor yeast. Its respiration via the tricarboxylic acid pathway (Suarez-Lepez and Inigo-Leal, 2004) provides the main source of carbon and energy. Acetaldehyde is the main organic byproduct of ethanol metabolism, but other volatile compounds, notably acetic acid, butanediol, diacetyl, and acetoin, can also be formed. In addition,... 

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. 

Cell culture studies have shown that aldehydic products derived from ethanol metabolism and lipid peroxidation can increase collagen mRNA levels and enhance the expression of connective tissue proteins. Acetaldehyde is able to increase the production of several extracellular matrix components. Studies also show that hepatic stellate cells, which are the primary source of extracellular matrix, become readily activated under conditions involving enhanced oxidative stress and lipid peroxidation. 

Antabuse, a drug given to alcoholics to prevent them from consuming alcoholic beverages, acts by interfering with the normal oxidation of ethanol. Antabuse inhibits the oxidation of acetaldehyde to the acetate anion. Because the first step in ethanol metabolism occurs but the second does not, the concentration of acetaldehyde rises, causing an individual to become violently ill. 

The second pathway for ethanol metabolism is called the ethanolinducible microsomal ethanol-oxidizing system (MEOS). This cytochrome P450-dependent pathway (Section 26.4.2) generates acetaldehyde and subsequently acetate... 

Acetaldehyde, produced from the metabolism of ethanol, may also be responsible for localized cancers, brain damage in prenatal infants, and growth suppression (in chicken embryos). Acetaldehyde, as a direct result of ethanol metabolism in the body, has been implicated in alcoholic cardiomyopathy and cancer of the digestive tract. The levels of acetaldehyde in blood are directly correlated with ethanol consumption. 

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. 

These pyrolysis products were also found in roasted tea and brandy-type alcoholic beverages (Sugimura and Sato, 1983). In addition, as a result of ethanol metabolism, mutagenic acetaldehyde is formed, while in coffee and tea caffeine, an inhibitor of DNA repair synthesis is present and may also contribute to cancer risk. 

When the ink-cap mushroom Coprinus atramentarius is eaten alone it is not toxic. However, if it is eaten with alcohol it induces an over-sensitivity that is similar to that of the drug disulphiram (antabuse). The fresh mushroom contains about 160 mg kg of the active component, coprine (9.34). This was shown to be A -(l-hydroxycyclopropyl)-L-glutamine, which contains the unusual Wacyl-l-aminocyclopropanol unit. It is metabolized to L-glutamic acid and cyclopropanone. The hydrate of cyclopropanone is a good inhibitor of acetaldehyde dehydrogenase. This induces elevated levels of acetaldehyde in the blood and retards the rate of ethanol metabolism. 

We are going to model the metabolism of ethanol in the human body using fundamental reaction kinetics along with five compartments to represent the human body. Alcohol (Ac) and acetaldehyde (De) will flow between these companments. but the alcohol and aldehyde will only be metabolized in the liver compartment. Alcohol and acetaldehyde are metabolized in the liver by the following series reactions. 

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). 

Ethanol is metaboli/ed to acetaldehyde by two main pathways (Fig. 2). The alcohol dehydrogenase route is operational when the blood alcohol concentration is in the range 1-5 mmol/1. Above this most of the ethanol is metaboli/ed via the microsomal P450 system. Although the end product in both cases is acetaldehyde, the side effects of induced P450 can be significant. Ethanol metabolism and excretion in a nomial 70 kg man is summari/.ed in Figure 3. 

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... 

Al Martini was not able to clear his blood ethanol rapidly enough to stay within the legal limit for driving. Ethanol is cleared from the blood at about Vz ounce/hr (15 mg/dL per hour). Liver metabolism accounts for more than 90% of ethanol clearance from the blood. The major route of ethanol metabolism in the liver is the enzyme liver alcohol dehydrogenase (ADH), which oxidizes ethanol to acetaldehyde with generation of NADH. 

Ethanol metabolism may result in alchohol-induced liver disease, including hepatic steatosis (fatty liver), alcohol-induced hepatitis, and cirrhosis. The principal toxic products of ethanol metabolism include acetaldehyde and free radicals. Acetaldehyde forms adducts with proteins and other compounds. The hydroxyethyl radical produced by MEOS and other radicals produced during... 

---