Cimetidine and other H2-receptor antagonists as inhibitors of human E3 aldehyde dehydrogenase.

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 gamma-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 Ki values of 1.1 +/- 0.2 microM and 1.0 +/- 0.0 microM, 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 Ki value of the E3 isozyme for cimetidine was the same as the in vitro dissociation constant for the H2-receptor.