Inhibition of Human Mitochondrial Aldehyde Dehydrogenase by Metabolites of Disulfiram and Structural Characterization of the Enzyme Adduct by HPLC-Tandem Mass Spectrometry

  • Dennis C. Mays
  • Andy J. Tomlinson
  • Kenneth L. Johnson
  • Jennifer Lam
  • James J. Lipsky
  • Stephen Naylor
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 463)

Abstract

Ingest of disulfiram blocks the metabolism of acetaldehyde, the product of ethanol metabolism, by inhibiting hepatic mitochondrial aldehyde dehydrogenase (ALDH2), a key ene by virtue of its low Km for acetaldehyde (Mascher & Kikuta, 1992; Greenfield & Pietruszko, 1977). Disulfiram is rapidly reduced in vivo to N,N-diethyldithiocarbamate (DDC) (Cobby et al., 1977) which is further metabolized as shown in Scheme 1. The general consensus is that disulfiram is too short-lived in vivo to account for the inhibition of ALDH2 that one its metabolites is the ultimate inhibitor (Yourick & Faiman, 1991; Hart & man, 1992).

Keywords

Glutathione Adduct Ketone NADH Sulfoxide 

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Copyright information

© Springer Science+Business Media New York 1999

Authors and Affiliations

  • Dennis C. Mays
    • 1
  • Andy J. Tomlinson
    • 2
  • Kenneth L. Johnson
    • 2
  • Jennifer Lam
    • 1
  • James J. Lipsky
    • 1
  • Stephen Naylor
    • 1
    • 2
  1. 1.Department of PharmacologyClinical Pharmacology UnitUSA
  2. 2.Department of Biochemistry and Molecular Biology Mayo Clinic and FoundationBiomedical Mass Spectrometry FacilityRochesterUSA

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