Alcohol dehydrogenase methanol poisoning

The first treatment for methanol poisoning, as in all critical poisoning situations, is support of respiration. There are three specific modalities of treatment for severe methanol poisoning suppression of metabolism by alcohol dehydrogenase to toxic products, hemodialysis to enhance removal of methanol and its toxic products, and alkalinization to counteract metabolic acidosis. 

As with methanol poisoning, early fomepizole or ethanol infusion and hemodialysis are standard treatments for ethylene glycol poisoning. Fomepizole, an inhibitor of alcohol dehydrogenase, has FDA approval for treatment of ethylene glycol poisoning in adults based on its ability to decrease concentrations of toxic metabolites in blood and urine and to prevent... 

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... 

Methyl alcohol is poisonous and is commonly used to denature ethyl alcohol. Methanol poisoning results from ingestion, inhalation of methanol vapors, or absorption through the skin. Methanol is transformed in the body to formaldehyde (H2CO) by the enzyme alcohol dehydrogenase. The formaldehyde is then metabolized to formic acid (HCOOH)... 

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... 

Ingestion of methanol, particularly during the prohibition era, resulted in significant illness and mortality. Where epidemics of methanol poisoning have been reported, one-third of the exposed population recovered with no ill effects, one-third have severe visual loss or blindness, and one-third have died. Methanol itself is not responsible for the toxic effects but is rapidly metabolized in humans by alcohol dehydrogenase to formaldehyde, which is subsequently metabolized by aldehyde dehydrogenase to form... 

Caution of Methyl Alcohol (Wood Alcohol) Methanol is commonly added to the rectified spirit, which makes it unfit to drink. Mixing methanol with alcoholic beverages results in methanol poisoning. Methanol is metabolized to formaldehyde and formic acid by aldehyde dehydrogenase. High blood levels (750 mg/dL) cause severe poisoning, which leads to blindness and even death. 

Poisoning by ethylene glycol (CH2OHCH2OH) is due to aldehydes, glycolate, oxalate, and lactate, resulting from an initial attack by alcohol dehydrogenase. This is similar to the activation of methanol to formaldehyde and subsequent oxidation by aldehyde dehydrogenase to formic acid. 

Because alcohol dehydrogenase has a higher affinity for ethanol than methanol, methanol poisoning is treated by giving ethanol to the afflicted individual. With both methanol and ethanol in the patient s system, alcohol dehydrogenase reacts more readily with ethanol, allowing the methanol to be excreted unchanged without the formation of methanol s toxic oxidation products. 

Any two compounds which are metabolized by the same enzyme may competitively inhibit the metabolism of the other. The extent of this will depend on the affinity each compound has for the enzyme. One example where this is important toxicologically is in the treatment of ethylene glycol and methanol poisoning. Both of these compounds are toxic as a result of metabolism by the enzyme alcohol dehydrogenase (see Chapter 7). Consequently one method of treatment is to reduce this by administration of ethanol, which has a greater affinity for the enzyme and so reduces metabolism and toxicity. 

The treatment of methanol poisoning involves firstly the administration of an antidote, ethanol, which blocks metabolism. Ethanol competes with methanol for alcohol dehydrogenase as the enzyme has a greater affinity for ethanol. Methanol metabolism can be reduced by as much as 90% by an equimolar dose of ethanol and the half-life becomes extended to 46 h. 4-Methylpyrazole, which also binds to alcohol dehydrogenase, has been used successfully in monkeys to treat methanol poisoning, as has folic acid. 

Side note Methanol Poisoning. An interesting and imponant example competitive substrate inhibition is the enzyme alcohol dehydrogenase (AC in the presence of ethanol and methanol. If a person ingests methanol, Al will convert it to formaldehyde and then formate, which causes blindne Consequently, the treatment involves intravenously injecting ethanol (wh is metabolized at a slower rate than methanol at a controlled rate to tie ADH to slow the metabolism of methanol-to-formaldehyde-to-formate so l the kidneys have time to filter out the methanol which is then excreted in urine. With this treatment, blindness is avoided. For more on the met nol/ethanol competitive inhibition, see Problem P7 2Sc. 

The emergency room treatment for methanol poisoning is to inject ethanol intravenously to tie up the alcohol dehydrogenase enzyme so that methanol will not be converted to formic acid and formate, which causes blindness. The goal of this open-ended problem is to build on the physiological-based model for ethanol metabolism to predict the ethanol injection rate for methanol poisoning. One can find a start on this problem by reading problem P7-25c. 

Figure 23-2. The oxidation of alcohols by alcohol dehydrogenase results in the formation of metabolites that cause serious toxicities. Ethanol, a preferred substrate for ADH, is used in methanol or ethylene glycol poisoning to slow the rate of formafion of fhe toxic metabolites of these alcohols. Acetaldehyde formed from ethanol is oxidized rapidly by aldehyde dehydrogenase except in the presence of disuifiram.

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