Cimetidine inhibition of human gastric and liver alcohol dehydrogenase isoenzymes: Identification of inhibitor complexes by kinetics and molecular modeling

Carol L. Stone, Thomas Hurley, Cara F. Peggs, Natalia Y. Kedishvili, Gerard J. Davis, Holly R. Thomasson, Ting Kai Li, William F. Bosron

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Cimetidine, an H2-receptor 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 χχ alcohol dehydrogenase isoenzymes was observed. Cimetidine inhibited all isoenzymes studied except χχ; the χχ 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 ππ 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.

Original languageEnglish
Pages (from-to)4008-4014
Number of pages7
JournalBiochemistry
Volume34
Issue number12
StatePublished - 1995

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Molecular modeling
Alcohol Dehydrogenase
Cimetidine
Liver
Isoenzymes
Stomach
Kinetics
Ethanol
Nizatidine
Oxidation
Histamine H2 Receptors
Acetaldehyde
NAD
Binding Sites
Famotidine
Thiazoles
Ranitidine
Enzymes
Pharmaceutical Preparations
Drinking

ASJC Scopus subject areas

  • Biochemistry

Cite this

Stone, C. L., Hurley, T., Peggs, C. F., Kedishvili, N. Y., Davis, G. J., Thomasson, H. R., ... Bosron, W. F. (1995). Cimetidine inhibition of human gastric and liver alcohol dehydrogenase isoenzymes: Identification of inhibitor complexes by kinetics and molecular modeling. Biochemistry, 34(12), 4008-4014.

Cimetidine inhibition of human gastric and liver alcohol dehydrogenase isoenzymes : Identification of inhibitor complexes by kinetics and molecular modeling. / Stone, Carol L.; Hurley, Thomas; Peggs, Cara F.; Kedishvili, Natalia Y.; Davis, Gerard J.; Thomasson, Holly R.; Li, Ting Kai; Bosron, William F.

In: Biochemistry, Vol. 34, No. 12, 1995, p. 4008-4014.

Research output: Contribution to journalArticle

Stone, CL, Hurley, T, Peggs, CF, Kedishvili, NY, Davis, GJ, Thomasson, HR, Li, TK & Bosron, WF 1995, 'Cimetidine inhibition of human gastric and liver alcohol dehydrogenase isoenzymes: Identification of inhibitor complexes by kinetics and molecular modeling', Biochemistry, vol. 34, no. 12, pp. 4008-4014.
Stone, Carol L. ; Hurley, Thomas ; Peggs, Cara F. ; Kedishvili, Natalia Y. ; Davis, Gerard J. ; Thomasson, Holly R. ; Li, Ting Kai ; Bosron, William F. / Cimetidine inhibition of human gastric and liver alcohol dehydrogenase isoenzymes : Identification of inhibitor complexes by kinetics and molecular modeling. In: Biochemistry. 1995 ; Vol. 34, No. 12. pp. 4008-4014.
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