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.
Higuchi
T
T
Faculty of Pharmaceutical Sciences, Kumamoto University, Japan.
Imamura
Y
Y
Otagiri
M
M
D000429:Alcohol Oxidoreductases / Q000037:antagonists & inhibitors*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001578:Benzopyrans / Q000494:pharmacology; D002227:Carbazoles / Q000494:pharmacology*; D007668:Kidney / Q000201:enzymology*; D007700:Kinetics; D009249:NADP / Q000378:metabolism / Q000494:pharmacology; D010666:Phenylpropionates / Q000494:pharmacology; D011422:Propionates / Q000494:pharmacology; D011817:Rabbits; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001578:Benzopyrans; D002227:Carbazoles; D010666:Phenylpropionates; D011422:Propionates; C043940:pyranoprofen; D009249:NADP; D000429:Alcohol Oxidoreductases; C007005:carprofen; C008924:pirprofen