PMID: 9185327May 1, 1997Paper

The effects of disulfiram and related compounds on equine hepatic alcohol dehydrogenase

Comparative Biochemistry and Physiology. Part C, Pharmacology, Toxicology & Endocrinology
B T Langeland, J S McKinley-McKee

Abstract

The reversible inhibition and the irreversible inactivation of equine hepatic alcohol dehydrogenase by disulfiram have been investigated. Disulfiram was found to be a potent competitive reversible inhibitor with KEO,I values at pH 7.0 and 10.0 of 50 microM and 30 microM, respectively. Reversible monodentate binding to the active site zinc is indicated by comparison with related compounds. Disulfiram was also found to chemically modify and inactivate the enzyme in an irreversible reaction, which proceeds via the formation of a reversible enzyme-disulfiram binary complex with a dissociation constant at pH 7.0 of 30 microM. The inactivation reaction has been studied over the pH 6.0 to 10.0 range. The dissociation constants for binding to the enzyme and the apparent first-order rate constants for inactivation have been determined as a function of pH. A pKa of 8.3 for the free enzyme has been assigned to the zinc-water ionization. Similar inhibition and affinity labelling kinetics are exhibited by diethyldithiocarbamate and by 2,2'- and 4,4'-dipyridyl disulphide, which have similar enzyme "on" velocity pKa values of 8.3 and 8.2, respectively. The enzyme is competitively protected from inactivation with disulfiram by 2,2'-dipyridyl, ...Continue Reading

References

Jan 1, 1992·Acta Psychiatrica Scandinavica. Supplementum·E N Petersen
May 1, 1967·Proceedings of the National Academy of Sciences of the United States of America·D E DrumB L Vallee
Oct 1, 1969·European Journal of Biochemistry·C H Reynolds, J S McKinley-McKee
Mar 1, 1967·Archives of Biochemistry and Biophysics·D R Grassetti, J F Murray
Apr 15, 1994·European Journal of Biochemistry·R I LindstadJ S McKinley-McKee
Jun 1, 1994·Archives of Biochemistry and Biophysics·H ReiersenJ S McKinley-McKee
Jan 1, 1996·Alcohol and Alcoholism : International Journal of the Medical Council on Alcoholism·B T Langeland, J S McKinley-McKee
Jul 1, 1975·Plant Physiology·D T Ho, J G Scandalios

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