Cimetidine Inhibition of Human Gastric and Liver Alcohol Dehydrogenase Isoenzymes: Identification of Inhibitor Complexes by Kinetics and Molecular Modeling

Academic Article

Abstract

  • Cimetidine, an H2receptor antagonist, is one of the most commonly prescribed drugs in the world. It has been reported to increase blood alcohol concentrations in drinking individuals. To determine if this increase could be due to inhibition of alcohol dehydrogenase activity, the effect of the drug on ethanol oxidation by gastric σσ alcohol dehydrogenase and liver β2β2, ππ, and ϰϰ alcohol dehydrogenase isoenzymes was observed. Cimetidine inhibited all isoenzymes studied except ϰϰ the ϰϰ isoenzyme showed no inhibition up to 5 mM cimetidine. Inhibition of the alcohol dehydrogenase isoenzymes by the H2-receptor antagonists nizatidine, ranitidine, and famotidine was negligible. Docking simulations with the β2•NAD+·4-iodopyrazole X-ray structure indicated that cimetidine fit well into the substrate binding site. The substitution on the thiazole ring of nizatidine, however, prevented docking into the binding site. Cimetidine inhibition of ethanol oxidation by σσ and β2β2 was competitive with varied ethanol, exhibiting Ki values of 2.8 ± 0.4 mM and 0.77 ± 0.07 mM, respectively. Cimetidine inhibition of ethanol oxidation by nn was noncompetitive with varied ethanol (Ki = 0.50 ± 0.03 mM). Inhibition of ethanol oxidation by σσ and β2β2 with varied NAD+ was competitive. These results, together with the cimetidine inhibition kinetics of acetaldehyde reduction by σσ and β2β2, with either varied NADH or varied acetaldehyde, are consistent with cimetidine binding to two enzyme species. These species are free enzyme and the productive enzyme·NAD+ complex. © 1995, American Chemical Society. All rights reserved.
  • Published In

  • Biochemistry  Journal
  • Digital Object Identifier (doi)

    Author List

  • Stone CL; Hurley TD; Peggs CF; Kedishvili NY; Davis GJ; Thomasson HR; Li TK; Bosron WF
  • Start Page

  • 4008
  • End Page

  • 4014
  • Volume

  • 34
  • Issue

  • 12