UDPGlucuronosyltransferase: Substrate Specificity and Reactivation after Partial Separation from Other Membrane Components

Abstract

The oxidation of a foreign compound may lead to the formation of metabolites which are more active both chemically and biologically than the original compound. These metabolites are usually conjugated as carbohydrate, amino acid, or peptide derivatives that usually display low biological activity. Glucuronide formation is a common final step in the metabolism and inactivation of many foreign compounds in mammalian tissues since d-glucuronic acid residues can be attached to hydroxyl, carboxylic, amino, or thiol groups. The enzyme(s) catalyzing the synthesis of glucuronides (UDPglucuronosyltransferase, E.C. 2.4.1.17) are located in the same intracellular structure, i.e., the microsomes, as the enzymes catalyzing the first steps in the metabolism of foreign compounds (1). The glucuronide-forming capacity of a tissue sample may vary considerably depending on the structure and possibly also on the functional state of the membrane. Removing the outer layers of membrane preparations isolated from rat liver, for example, with trypsin (2) and chaotropic agents (3), or the perturbation of membrane structure with surfactants (2,4,5) or phospholipases (6,7) can each increase UDPglucuronosyltransferase activity with a simultaneous decrease in drug-hydroxylating activity.