EFFECT OF PRETREATMENT OF RABBITS WITH PHENOBARBITAL OR 3-METHYLCHOLANTHRENE ON THE DISTRIBUTION OF DRUG-METABOLIZING ENZYME ACTIVITY IN SUBFRACTIONS OF HEPATIC MICROSOMES

¹ Department of Pharmacology, University of Iowa, Iowa City, Iowa

Hepatic microsomes from control, phenobarbital-, and 3-methylchol-anthrene (3-MC)-pretreated rabbits have been separated into rough-surfaced microsomal subfractions (RSM) and smooth-surfaced microsomal subfraetions (SSM), and the drug- metabolizing enzyme activity of the subfractions has been determined. Depending upon the substrate studied, phenobarbitai pretreatment resulted in either no change in levels of drug-metabolizing enzyme activity or caused significant increases in levels of activity. Phenobarbital-induced increases in enzyme activity were generally seen to occur in both SSM and RSM. The effects of 3-MC pretreatment, however, were either increases or decreases in enzyme activity, depending upon the enzyme pathway studied. These effects were generally seen in one microsomal subfraction or the other but not in both fractions. When decreases in activity were observed after 3-MC, they were always seen in the SSM. Electron micrographs of microsomal subfractions showed that pretreatment of rabbits with phenobarbital did not significantly change the purity of the two subfractions. 3-MC administration was associated with an apparent change in time sedimentation characteristics of the smooth-surfaced vesicles so that contamination of the rough-surfaced pellet with ralatively large, smooth-surfaced vesicies was greatly increased. However, this change was not accompanied by strictly proportional decreases in enzyme activity in SSM and increases in RSM. Thus, 3-MC-induced changes in levels of enzyme activity in microsomal subfractions cannot be explained solely on the basis of changes in the morphologic purity of the two subfractions.