REDUCTASES FOR XENOBIOTIC CARBONYL COMPOUNDS. REDUCTASES FOR XENOBIOTIC CARBONYL COMPOUNDS. Structures and Specificities of the Human Liver Enzymes

Abstract

Dihydrodiol dehydrogenase (DD) is involved in both the metabolic inactivation and intoxication of aromatic hydrocarbons. Human liver contains four DDs, DD1-DD4, of which DD3 was identified with aldehyde reductase. In order to further evaluate the nature of the other enzymes, we performed the molecular cloning of the two enzymes, DD2 and DD4, and examined the reactivity towards endogenous and xenobiotic compounds. cDNA cloning of the enzymes demonstrated significant sequence homology to members of the aldo-keto reductase family. The sequences of DD2 and DD4, having 82% identity, were virtually identical with those of human liver bile-acid binder and chlordecone reductase, respectively. The results of substrate specificity for endogenous compounds indicated that DD1, DD2 and DD4 act as 3(20)α or 3α-hydroxysteroid dehydrogenases, and suggested that DD1 and DD2 are also the major species of prostaglandin D2 11-ketoreductase in human liver cytosol. On the other hand, the DDs catalyzed the reduction of several drug ketones more efficiently than did aldehyde reductase and carbonyl reductase of human liver.