Inhibition of a major NAD(P)-linked oxidoreductase from rat liver cytosol by steroidal and nonsteroidal anti-inflammatory agents and by prostaglandins.
A NAD(P)-linked 3 alpha-hydroxysteroid dehydrogenase [3 alpha-hydroxysteroid: NAD(P) oxidoreductase, EC 1.1.1.50], purified to homogeneity from male rat liver cytosol, accounts for most of the oxidative activity for 3 alpha-hydroxysteroids and for benzenedihydrodiol (trans-1,2-dihydroxy-3,5-cyclohexadiene) of this tissue. This enzyme, which also promotes the reduction of quinones and certain aromatic aldehydes and ketones, is powerfully inhibited by the major types of nonsteroidal and steroidal anti-inflammatory drugs. The IC50 values for indomethacin and for betamethasone are in the low micromolar range. The rank order of the inhibitory potencies of a series of these agents paralleled closely that reported for the inhibition of cyclooxygenase by nonsteroidal anti-inflammatory agents or the indirect inhibition of phospholipase A2 by anti-inflammatory steroids. A good correlation is found also between the logarithm of the concentrations of these drugs required to inhibit 3 alpha-hydroxysteroid dehydrogenase and the human anti-inflammatory dose. The suggestion that this enzyme may play a role in mediating inflammation is further strengthened by the observation that the dehydrogenase binds arachidonic acid and is also potentially inhibited by certain prostaglandins. This enzyme may be of use in the evaluation of anti-inflammatory activity.
D015096:3-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors*; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific); D000305:Adrenal Cortex Hormones / Q000494:pharmacology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D016861:Cyclooxygenase Inhibitors; D003600:Cytosol / Q000201:enzymology; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D008297:Male; D008968:Molecular Conformation; D011453:Prostaglandins / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
D000305:Adrenal Cortex Hormones; D000893:Anti-Inflammatory Agents; D016861:Cyclooxygenase Inhibitors; D011453:Prostaglandins; D015096:3-Hydroxysteroid Dehydrogenases; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific)