Cimetidine inhibition of human gastric and liver alcohol dehydrogenase isoenzymes: identification of inhibitor complexes by kinetics and molecular modeling.
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 sigma sigma alcohol dehydrogenase and liver beta 2 beta 2, pi pi, and chi chi alcohol dehydrogenase isoenzymes was observed. Cimetidine inhibited all isoenzymes studied except chi chi; the chi chi 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 beta 2.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 sigma sigma and beta 2 beta 2 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 pi pi was noncompetitive with varied ethanol (Ki = 0.50 +/- 0.03 mM). Inhibition of ethanol oxidation by sigma sigma and beta 2 beta 2 with varied NAD+ was competitive. These results, together with the cimetidine inhibition kinetics of acetaldehyde reduction by sigma sigma and beta 2 beta 2, 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.
Stone
C L
CL
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis 46202-5122.
Hurley
T D
TD
Peggs
C F
CF
Kedishvili
N Y
NY
Davis
G J
GJ
Thomasson
H R
HR
Li
T K
TK
Bosron
W F
WF
D000426:Alcohol Dehydrogenase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D001667:Binding, Competitive; D002927:Cimetidine / Q000737:chemistry / Q000494:pharmacology*; D015738:Famotidine / Q000737:chemistry / Q000494:pharmacology; D005753:Gastric Mucosa / Q000201:enzymology*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000737:chemistry; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D008433:Mathematics; D008958:Models, Molecular; D009243:NAD / Q000378:metabolism; D016567:Nizatidine / Q000737:chemistry / Q000494:pharmacology; D011899:Ranitidine / Q000737:chemistry / Q000494:pharmacology; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D013329:Structure-Activity Relationship
D007527:Isoenzymes; D011994:Recombinant Proteins; D009243:NAD; D015738:Famotidine; D002927:Cimetidine; D011899:Ranitidine; D000426:Alcohol Dehydrogenase; D016567:Nizatidine