Increase in Levels of Glucuronylating Enzymes and Associated Rise in Activities of Mitochondrial Oxidative Enzymes Upon Phenobarbital Administration in the Rat

Previous papers from this and other laboratories have dealt with the increase of drug-metabolizing activities of liver microsomes by administration of certain drugs and with the metabolic events associated with this increase (1). Heretofore, in this laboratory the greatest amount of attention has been given to drug hydroxylation, although this is only one of a number of detoxicating systems that can be stimulated by the administration of drugs. In the present paper we describe studies with another detoxicating system which can be stimulated by drug administration, namely the glucuronylating system. We also describe studies on other metabolic events occurring in association with drug administration, namely increases in the activities of mitochondrial oxidative enzymes. The glucuronylating pathway is one of the most important routes for drug detoxication. A great many drugs and foreign products, as well as natural products, are excreted in the urine as glucuronides, by direct esterificadon or after prior hydroxylation. The glucuronylation pathway has been well defined and is given in outline in Fig. 1. The first enzyme involved, UDPG 1 dehydrogenase, is a supernatant enzyme. It has been purified by Strominger et al. (2). The second enzyme, glucu-1Abbreviations employed in this paper: UDPG, Uridine diphosphoglucose; UDPGA, Uridine diphosphoglucuronic acid; NAD +, nicotinamide adenine dinueleotide; NADP +, nicotinamide adenine dinucleotide phosphate; ADP, Adenosine diphosphate; DCPIP, 2,6-dichlorophenolindophenol. ronyl transferase, is a microsomal enzyme which has been studied extensively by Isselbacher and his associates (3). UDPG UDPG + 2 NAD + dehydrogenase) UDPGA