Alcohol metabolism Enzymes

Yamauchi M, Maezawa Y, Mizuhara Y et al. Polymorphisms in alcohol metabolizing enzyme genes and alcoholic cirrhosis in Japanese patients. Hepatology 1995 22 1136-1142. 

Yoshida A (1993) Genetic polymorphisms of alcohol-metabolizing enzymes related to alcohol sensitivity and alcoholic diseases. In Lin KM, Poland RE, Nakasaki G (eds) Psychopharmacology and psychobiology of ethnicity. American Psychiatric Press, Washington, pp 169-186... 

Maezawa Y, Yamauchi M, Toda G, Suzuki H, Sakurai S. Alcohol-metabolizing enzyme polymorphisms and alcoholism in Japan. Alcohol Clin Esp Res 1995 19 951-954. 

Tsuruoka, N., Kidokoro, A., Matsumoto, I., and Abe, K. 2005. Modulating effect of sesame, a functional lignan in sesame seeds, on the transcriptions levels of lipid-and alcohol-metabolizing enzymes in rat liver a DNA microarray study. Biosci BiotechnolBiochem 69 179-188. 

Both ADH and ALDH use NAD+ as cofactor in the oxidation of ethanol to acetaldehyde. The rate of alcohol metabolism is determined not only by the amount of ADH and ALDH2 enzyme in tissue and by their functional characteristics, but also by the concentrations of the cofactors NAD+ and NADH and of ethanol and acetaldehyde in the cellular compartments (i.e., cytosol and mitochondria). Environmental influences on elimination rate can occur through changes in the redox ratio of NAD+/NADH and through changes in hepatic blood flow. The equilib-... 

Alcohol metabolism (Figure 6.37) occurs mainly through oxidative pathways involving the enzymes alcohol dehydrogenase (ADH), acetaldehyde dehydrogenase (ALDH),... 

The chiral compounds (/ )- and (5)-bis(trifluoromethyl)phenylethanol are particularly useful synthetic intermediates for the pharmaceutical industry, as the alcohol functionality can be easily transformed without a loss of stereospecificity and biological activity, and the trifluoromethyl functionalities slow the degradation of the compound by human metabolism. A very efficient process was recently demonstrated for the production of the (5)-enantiomer at >99% ee through ketone reduction catalyzed by the commercially available isolated alcohol dehydrogenase enzyme from Rhodococcus erythropolis (Figure 9.1). The (7 )-enantiomer could be generated at >99% ee as well using the isolated ketone reductase enzyme KRED-101. 

Other metabolic enzymes that show polymorphic differences in that they can occur as genetic high-activity and low-activity variants include acetylcholinesterase, butyrylcholinesterases, flavin-dependent monooxygenase, alcohol dehydrogenase, epoxide hydrolase, and arylesterase (Beltoft et al. 2001). 

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... 

There are some clinically important pharmacodynamic drug-drug interactions to be mentioned. Antipsychotics will potentiate the central depressant effects of sedatives and of alcohol. They will also increase the risk of respiratory-depressant effects of opiates. Inducers of drug metabolic enzymes like for example rifampicin and several antiepileptics, may increase the elimination rate of antipsychotic agents and thus decrease their efficacy. 

Sustained-release formulations can produce stable serum concentrations with once or twice daily dosage. Therapeutic effects occur at blood levels > 5 mg/1, and side effects increase considerably at levels > 15 mg/1. Smoking, alcohol, anticonvulsants, and rifampicin induce the drug-metabolizing enzyme system in liver and reduce the half-life of theophylline. On the other hand, heart and liver failure, sustained fever, old age and drugs such as cimeti-dine, ciprofloxacin, and oral contraceptives reduce theophylline clearance and thereby increase serum concentrations. 

Cinnamyl anthranilate has the characteristic effects of a peroxisome proliferator on mouse liver, increasing the activity of peroxisomal fatty acid-metabolizing enzymes and microsomal CYP4A and increasing hepatocellular proliferation. These effects are mediated by the intact ester, and were not seen after administration of the hydrolysis products, cinnamyl alcohol and anthranilic acid. The corresponding effects on rat liver were very much weaker. No relevant data from humans were available. 

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. 

This is known as Michaelis-Menten or saturation kinetics. The processes that involve specific interactions between chemicals and proteins such as plasma protein binding, active excretion from the kidney or liver via transporters, and metabolism catalyzed by enzymes can be saturated. This is because there are a specific number of binding sites that can be fully occupied at higher doses. In some cases, cofactors are required, and their concentration may be limiting (see chap. 7 for salicylate, paracetamol toxicity). These all lead to an increase in the free concentration of the chemical. Some drugs, such as phenytoin, exhibit saturation of metabolism and therefore nonlinear kinetics at therapeutic doses. Alcohol metabolism is also saturated at even normal levels of intake. Under these circumstances, the rate of... 

There are certain limitations with cosolvent approach, as with any other approaches, as poor tasting cosolvent (PG), adverse physiological effects (e.g., alcohol) and potential of cosolvent on metabolic enzymes, transporters, and distribution and hence unintentionally altering drug pharmacokinetic properties. For solubilized parenteral application, choice of cosolvents is further limited by physiological acceptance, as well as precipitation on injection and pain on administration. However, the approach remains popular both for oral as well as parenteral application as demonstrated by numerous commercial products. In addition, application of newer cosolvents is increasing to overcome some of these barriers. 

Many other significant polymorphisms in xenobiotic metabolizing enzymes have been described, including those for several CYP genes, alcohol and aldehyde dehydrogenases, epoxide hydrolase, and paraoxonase. One interesting polymorphism affecting... 

A common step in the metabolism of alcohols is carried out by alcohol dehydrogenase enzymes that produce aldehydes from primary alcohols that have the -OH group on an end carbon and produce ketones from secondary alcohols that have the -OH group on a middle carbon, as shown by the examples in Reactions 7.3.6 and 7.3.7. As indicated by the double arrows in these reactions, the reactions are reversible and the aldehydes and ketones can be converted back to alcohols. The oxidation of aldehydes to carboxylic acids occurs readily (Reaction 7.3.8). This is an important detoxication process because aldehydes are lipid soluble and relatively toxic, whereas carboxylic acids are more water soluble and undergo phase n reactions leading to their elimination. 

Higuchi S. Polymorphisms of ethanol metabolizing enzyme genes and alcoholism. Alcohol Alcohol 1994 (Suppl 2) 29-34. 

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