Cytosolic alcohol dehydrogenase

Yeast contains two cytosolic alcohol dehydrogenase isoenzymes.66 Alcohol dehydrogenase I, present in large amounts in cells undergoing fermentation,... 

Cytosolic alcohol dehydrogenases only act on free retinol, not retinol bound to CRBP, so they are unlikely to he involved in formation of retinaldehyde and retinoic acid. Furthermore, inhihition of cytosolic alcohol dehydrogenases does not inhibit the oxidation of retinol to retinoic acid (Boerman and Napoli, 1996). CRBP-bound retinol is a substrate for atleast three microsomal NADP+-dependent dehydrogenases hut, given the intracellular NADP+ NADPH ratio (0.01, compared with an NAD+ NADH ratio of the order of 10 ), it is likely that these microsomal enzymes wiU act mainly to reduce retinaldehyde to retinol and not to oxidize retinol. 

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). 

Walsh JS, Reese MJ, Thurmond LM. The metabolic activation of abacavir by human liver cytosol and expressed human alcohol dehydrogenase isozymes. Chem Biol Interact 2002 142(1-2) 135-154. 

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. 

The primary pathway for alcohol metabolism involves alcohol dehydrogenase (ADH), a cytosolic enzyme that catalyzes the conversion of alcohol to acetaldehyde (Figure 23-1, left). This enzyme is located mainly in the liver, but small amounts are found in other organs such as the brain and stomach. In some Asian populations with polymorphisms in ADH that affect enzyme activity, a form of ADH with reduced activity is associated with an increased risk of alcoholism. 

For foreign compounds, the majority of oxidation reactions are catalyzed by monooxygenase enzymes, which are part of the mixed function oxidase (MFO) system and are found in the SER (and also known as microsomal enzymes). Other enzymes involved in the oxidation of xenobiotics are found in other organelles such as the mitochondria and the cytosol. Thus, amine oxidases located in the mitochondria, xanthine oxidase, alcohol dehydrogenase in the cytosol, the prostaglandin synthetase system, and various other peroxidases may all be involved in the oxidation of foreign compounds. 

Alcohol and aldehyde oxidation. Although a microsomal enzyme system has been demonstrated, which oxidizes ethanol (see above), probably the more important enzyme in vivo is alcohol dehydrogenase, which is a cytosolic enzyme (soluble fraction) and is found in the liver and also in the kidney and the lung. 

Other types of reduction catalyzed by non-microsomal enzymes have also been described for xenobiotics. Thus, reduction of aldehydes and ketones may be carried out either by alcohol dehydrogenase or NADPH-dependent cytosolic reductases present in the liver. Sulfoxides and sulfides may be reduced by cytosolic enzymes, in the latter case involving glutathione and glutathione reductase. Double bonds in unsaturated compounds and epoxides may also be reduced. Metals, such as pentavalent arsenic, can also be reduced. 

Kemper and Elfarra (1996) demonstrated the oxidation of butenediol by hepatic alcohol dehydrogenase (ADH), yielding 1-hydroxy-2-butanone as a single stable metabolite various intermediates have been proposed. For the ADH-dependent oxidation of racemic butenediol in liver cytosol of male B6C3Fj mice, male Sprague-Dawley rats and three humans, saturation kinetics were found. The ratio was similar in these... 

The mitochondrial inner membrane has no transport system for NAD+ or NADH. In animal cells, most of the NADH that must be oxidized by the respiratory chain is generated in the mitochondrial matrix by the TCA cycle or the oxidation of fatty acids. However, NADH also is generated by glycolysis in the cytosol. If 02 is available, it clearly is advantageous to reoxidize this NADH by the respiratory chain, rather than by the formation of lactate or ethanol as described in chapter 12. This is evident from the findings that approximately 2.5 molecules of ATP can be formed for each NADH oxidized in the mitochondria, whereas no ATP is made when NADH is oxidized by the cytosolic lactate dehydrogenase or alcohol dehydrogenase. 

Cytosol easy to use, cheap addition of cofactors (simple mixtures), Only not membrane-bound metabolizing enzymes such as alcohol dehydrogenases, sulfotransferases, glutathione S transferase, N-acetyl transferases partial metabolic profile, induction not modeled... 

Alcohol dehydrogenase, a cytosolic enzyme, catalyzes the oxidation of ethanol to acetaldehyde with the generation of NADH. The energy from this NADH is transferred to mitochondria, primarily by means of the malate-aspartate shuttle. When an alcoholic consumes over 50% of his or her energy in the form of alcohol, this shuttle becomes vastly important. Most of the acetaldehyde is oxidized in the mitochondria by mitochondrial aldehyde dehydrogenase, though a cytosolic version of the enzyme also exists. These reactions are shown in Figure 4.69. 

Methoxyethanol is rapidly absorbed through the skin and lungs into the blood. Its water solubility favors distribution to all body tissues except adipose tissue. Metabolism occurs via two pathways. Methoxyethanol is a substrate for alcohol dehydrogenase, and the resultant methoxyacetaldehyde is metabolized to methoxyacetic acid by aldehyde dehydrogenase. In rats, pretreatment with phenobarbitol decreased formation of methoxyacetaldehyde but accelerated formation of methoxyacetate in liver cytosolic fractions. A minor pathway involves demethylation by undefined enzymes to ethylene glycol and CO2. 

Alcohol dehydrogenase Cytosol, blood, microsomes Carbonyl reduction NAD+ 1 [110] [111]... 

Lack phase II cytosolic enzymes (glutathione S-transferase, sulfotransferases, alcohol dehydrogenase, xanthine oxidase, etc.)... 

Alcohol dehydrogenases (ADH), which are zinc enzymes found in the cytosol of the mammalian liver and in various extrahepatic tissues. 

---