CHARACTERIZATION OF CARBONYL REDUCTASES PURIFIED FROM RABBIT LIVER, KIDNEY AND HEART AS DRUG-METABOLIZING ENZYME

Abstract

Carbonyl reductases were purified from the cytosolic fraction of rabbit liver, kidney and heart by using acetohexamide as a substrate. The enzymes purified from the liver and kidney reduced many drugs with a ketone group. However, the enzyme purified from the heart had no ability to reduced drugs with a ketone group other than acetohexamide. A correlation was observed between the values of the specificity constant (kcat / Km) of the enzymes purified from the liver and kidney for 4-acetylpyridine analogs substituted by straight-chain alkyl groups and their partition coefficients. These results indicate that the hydrophobicity of 4-acetylpyridine analogs plays an inportant role in the catalytic activity and substrate-binding capacity of these enzymes. Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibited the enzyme purified from the kidney noncompetitively with respect to acetohexamide and competitively with respect to NADPH. It is reasonable to postulate that NSAIDs cause the inhibition of acetohexamide reduction by competing with NADPH.