Stereoselective inhibition of carbonyl reductase from rabbit kidney by enantiomers of carprofen.

The inhibitory effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on the reduction of acetohexamide catalyzed by carbonyl reductase from rabbit kidney were examined. Of NSAIDs tested, only carprofen exhibited a pronounced stereoselectivity for the inhibition of the purified enzyme; (-)-carprofen inhibited more strongly the enzyme than three fold of its (+)-form. (-)-Carprofen was found to inhibit the enzyme noncompetitively with respect to acetohexamide and competitively with respect to NADPH. Similar modes were observed for the inhibition of the enzyme by (+)-carprofen. The treatment of the apoenzyme with (-)-carprofen led to a time- and concentration-dependent loss of the catalytic activity. Furthermore, NADP+ afforded a significant protection against inactivation of the enzyme by (-)-carprofen. These results suggest that enantiomers of carprofen bind to coenzyme-binding domain of the enzyme and cause the stereoselective inhibition of acetohexamide reduction by competing with NADPH.