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Inhibition by alternate substrate, ethanol, and dead-end inhibitor 4-methylpyrazole (4MP; fomepizole) of ADH in combination with hemodialysis has been widely used for treatment of severe ethylene glycol and methanol poisonings.

Enzymatic activity was initiated in all the members of the human ADH family.

The corresponding kinetic parameters was determined and used to simulate the effectiveness of the inhibitors at pharmacologically relevent alcohol levels in the context of the ADH family.

Conclusion

Questions???

Thank you...and Drink Responsibly.

  • Shou-Lun Lee, Hsuan-Ting Shih, Yu-Chou Chi, Yeung-Pin Li, Shih-Jiun Yin, Oxidation of methanol, ethylene glycol, and isopropanol with human alcohol dehydrogenases and the inhibition by ethanol and 4-methylpyrazole, Chemico-Biological Interactions, Volume 191, Issues 1–3, 30 May 2011, Pages 26-31, ISSN 0009-2797, 10.1016/j.cbi.2010.12.005. (http://www.sciencedirect.com/science/article/pii/S0009279710006423)
  • Jeffrey A. Kraut and Ira Kurtz. Toxic Alcohol Ingestions: Clinical Features, Diagnosis, and Management. CJASN January 2008 3): (1) 208-225; published ahead of print November 28, 2007, doi:10.2215/CJN.03220807

Oh yeah, references...

The accepted target plasma ethanol concentration for treatment of ethylene glycol and methanol poisoning is approximately 100mg/dl (21.7mM).

And one more thing...

Alcohol Dehydrogenase

  • EC 1.1.1.1
  • Alcohol dehydrogenase (ADH) catalyzes hydride transfer from substrate to the C4 carbon of the nicotinamide ring of NAD+, to produce the corresponding aldehyde. Hence, it is also referred to as Aldehyde reductase.
  • Steady state kinetic studies showed that 4-methylpyrazole (4-MP) was competitive inhibitor versus ethanol for most of the ADH family, but non-competitive against ethanol for three of the ADH family.
  • The efficacy of treatment of the toxic alcohol poisoning by ethanol or 4-MP may potentially vary for patients due to expression of certain ADH's.

Alcohol Dehydrogenase

  • In humans and many other animals, they serve to break down alcohols which are otherwise toxic, and they also participate in generation of useful aldehyde, ketone, or alcohol groups during biosynthesis of various metabolites.

Oxidation of methanol, ethylene glycol, and isopropanol with human alcohol dehydrogenases and the inhibition by ethanol and 4-methylpyrazole

Experiment Background

  • Intoxications with ethylene glycol, methanol, and isopropanol are among the most common ingestions. The toxicity is related to the production of toxic metabolites by ADH and aldehyde, that is, oxalate and glycolate from ethylene glycol and formate from methanol poisoning. Acetone from isopropanol is in contrast less toxic than the parent compound, isopropanol.

Ethanol & Toxic Alcohols

Methanol

Acetone

Tijani Osumah

Dept. of Chemistry & Biochemistry

University of Texas at Arlington

Isopropanol

Ethylene glycol

Ethanol

Dead-end inhibitor 4-methylpyrazole (fomepizole)

Experimental Methods

RESULTS

Inhibition of oxidation of (a) methanol (b) ethylene glycol (c) isopropanol by alternate substrate ethanol with human ADHs.

The data from the dead-end inhibition were fit with one of the following linear inhibition equations for either competitive or uncompetitive inhibitions.

RESULTS

Inhibition of (a) ethanol (b) methanol (c) ethylene glycol and (d) isopropanol by dead-end inhibitor 4-methylpyrazole with human ADHs.

RESULTS

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