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MOLECULAR PHARMACOLOGY 52:267-271 (1997).

Cimetidine and Other H₂-Receptor Antagonists as Inhibitors of Human E3 Aldehyde Dehydrogenase

Alexandra Kikonyogo and Regina Pietruszko

Center of Alcohol Studies and the Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, New Jersey 08855-0969

The histamine H₂-receptor antagonists have been identified as inhibitors of human liver aldehyde dehydrogenase (EC 1.2.1.3) isozymes, E1, E2, and E3. Inhibition was strongest with the E3 isozyme, whose substrates include -aminobutyraldehyde, the aldehyde metabolites of polyamines, and betaine aldehyde. Burimamide, metiamide, cimetidine guanidine, cimetidine, and tiotidine were competitive with aldehyde substrates and noncompetitive with the coenzyme, binding to both the free E3 isozyme and the enzyme·coenzyme binary complex. Cimetidine and tiotidine were the best inhibitors, with K_i values of 1.1 ± 0.2 µM and 1.0 ± 0.0 µM, respectively; both are the first ever described potent and selective inhibitors of the E3 isozyme. Examination of the H₂-receptor antagonist structures for insight into the moieties accounting for E3 isozyme inhibition pointed to the side-chain polar groups as strongly influencing inhibition, with the cyanoguanidine side chain of cimetidine and tiotidine having the strongest influence. The K_i value of the E3 isozyme for cimetidine was the same as the in vitro dissociation constant for the H₂-receptor.