Alcohol dehydrogenase inhibition

Horse Uver alcohol dehydrogenase Inhibited by aliphatic, cychc and aromatic oximes using ethanol as substrate 123... 

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... 

Figure 5 Model of phosphorus (P) deficiency-induced physiological changes associated with the release of P-mobilizing root exudates in cluster roots of white lupin. Solid lines indicate stimulation and dotted lines inhibition of biochemical reaction sequences or mclaholic pathways in response to P deliciency. For a detailed description see Sec. 4.1. Abbreviations SS = sucrose synthase FK = fructokinase PGM = phosphoglueomutase PEP = phosphoenol pyruvate PE PC = PEP-carboxylase MDH = malate dehydrogenase ME = malic enzyme CS = citrate synthase PDC = pyruvate decarboxylase ALDH — alcohol dehydrogenase E-4-P = erythrosc-4-phosphate DAMP = dihydraxyaceConephos-phate APase = acid phosphatase.

Intraperitoneal injection of 4-methylpyrazole to rats at 90 mg/kg BW, given 2 h prior to 1080 administration, offered partial protection against accumulations of citrate or fluorocitrate in the kidney (Feldwick et al. 1994). The antidotal effects of 4-methylpyrazole are attributed to its inhibition of NAD+-dependent alcohol dehydrogenase that converts l,3-difluoro-2-propanol to difluoro-acetone, an intermediate in the pathway of erythrofluorocitrate metabolism (Feldwick et al. 1994). A disadvantage of 4-methylpyrazole is that it needs to be administered before significant exposure to fluoroacetate. 

Fluoroethanol itself is innocuous towards a variety of tissue constituents, a series of enzymes in rat-liver mince, and the respiration and metabolism in liver, kidney, heart and brain slice.3 After a period of incubation in those tissues known to contain alcohol dehydrogenase, e.g. liver and kidney, the respiration and pyruvate oxidation were strongly inhibited. Likewise, following a period of incubation with yeast, acetate oxidation was blocked. These inhibitions were similar to those produced by fluoroacetate, and the facts can best be explained by the oxidation of fluoroethanol to fluoroacetic acid by alcohol dehydrogenase. 

Disulfiram (Antabuse). Disnlfiram is the only medication specifically approved by the FDA as an aversion therapy for snbstance abnse, specifically alcohol abnse or dependence. Disnlfiram s mechanism of action is qnite simple it is an inhibitor of alcohol dehydrogenase, the major enzyme responsible for the metabolism. Inhibiting this enzyme resnlts in the accnmnlation of acetylaldehyde. Acetylaldehyde is primarily responsible for many of the nnmistakable symptoms of a hangover, and when it accnmnlates in the presence of disnlfiram, it produces a constellation of very nncomfortable physical symptoms. 

Rate experiments that are typically carried out in the presence of different concentrations of an alternative product (or product analog) while using the normal substrates . This approach can be particularly useful when the normal product cannot be used because it is unstable, insoluble, or ineffective (the latter indicated by a very high Ki value). Moreover, the normal product may be consumed as an essential substrate in a coupled assay system for the primary enzyme. Fromm and Zewe used the alternative product inhibition approach in their study of hexokinase. Wratten and Cleland later applied this procedure to exclude the Theorell-Chance mechanism for liver alcohol dehydrogenase. See Abortive Complexes... 

A potent five-membered heterocyclic inhibitor (the chemical systematic name is 1,2-diazole) that strongly inhibits liver alcohol dehydrogenase. See Alcohol Dehydrogenase... 

Sharkawi M, Elfassy B. 1985. Inhibition of mouse liver alcohol dehydrogenase by methyl n-butyl ketone. Toxicol Lett 25 185-189. 

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. 

Methanol is converted to the toxic metabolites formaldehyde and formate by alcohol dehydrogenase and aldehyde dehydrogenase. By inhibiting alcohol dehydrogenase, ethanol and fomepizole reduce the formation of toxic metabolites. 

Fomepizole Inhibits alcohol dehydrogenase, prevents conversion of methanol and ethylene glycol to toxic metabolites Methanol and ethylene glycol poisoning Orphan drug. Toxicity Headache, nausea, dizziness, rare allergic reactions... 

Metabolism of ethylene glycol and methanol to their toxic products can be blocked by inhibiting the enzyme alcohol dehydrogenase with a competing drug, such as fomepizole (4-methylpyrazole). Ethanol is also an effective antidote, but it can be difficult to achieve a safe and effective blood level. 

The mechanism of toxicity of ethylene glycol involves metabolism, but unlike previous examples, this does not involve metabolic activation to a reactive metabolite. Thus, ethylene glycol is metabolized by several oxidation steps eventually to yield oxalic acid (Fig. 7.84). The first step is catalyzed by the enzyme alcohol dehydrogenase, and herein lies the key to treatment of poisoning. The result of each of the metabolic steps is the production of NADH. The imbalance in the level of this in the body is adjusted by oxidation to NAD coupled to the production of lactate. There is thus an increase in the level of lactate, and lactic acidosis may result. Also, the intermediate metabolites of ethylene glycol have metabolic effects such as the inhibition of oxidative phosphorylation, glucose metabolism, Krebs cycle, protein synthesis, RNA synthesis, and DNA replication. 

Methanol is a solvent, which is added to ethanol and sometimes used in antifreeze. The main target organ is the optic system resulting from metabolic inhibition and systemic toxicity due to metabolic acidosis from formate and lactate. Toxicity is due to metabolism to formic acid via alcohol dehydrogenase and insufficient detoxication via tetrahydrofolate. The overall result is circulus hypoxicus. Treatment involves blockade of metabolism with ethanol and treatment of metabolic acidosis (NaHCC>3). 

Uncompetitive inilibitors of liver alcohol dehydrogenase (Chapter 15) could be used to treat cases of poisoning by methanol or ethylene glycol.81 83 The aim is to prevent rapid oxidation to the toxic acids HCOOH and HOCH2COOH, which lower blood pH, while the alcohols are excreted. Uncompetitive inhibitors have an advantage over competitive inhibitors as therapeutic agents in that the inhibition is not overcome when the substrate concentration is saturating.84... 

The reactions of Eq. 15-19 occur nonenzymatically only under the influence of strong base but dehydrogenases often catalyze similar condensations relatively rapidly and reversibly. Pyruvate inhibits lactate dehydrogenase, 2-oxoglutarate inhibits glutamate dehydrogenase, and ketones inhibit a short-chain alcohol dehydrogenase in this manner.133,693... 

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