Further Studies on the Induction of the Drug-hydroxylating Enzyme System of Liver Microsomes

Further studies of the induction of the liver microsomal drug-hydroxylating enzyme system by pretreatment of rats with various drugs are presented. The phenobarbital-induced increase in the microsomal content of CO-binding pigment and in the activities of TPNH-cytochrome c reductase and the oxidative demethylation of aminopyrine is proportional, within certain limits, to the amount of phenobarbital injected. Removal of the inducer results in a parallel decrease in the levels of CO-binding pigment, TPNH-cytochrome c reductase, and aminopyrine demethylation. Other inducing drugs have been investigated and shown to act similarly to phenobarbital. The early increase in these enzymes is found in the microsomal subfraction consisting of rough-surfaced vesicles, whereas repeated administration of the inducing drug results in a concentration of the enzymes in the smooth-surfaced vesicles. The phenobarbital-stimulated formation of endoplasmic membranes is reflected in increased amounts of the various microsomal phospholipid fractions as revealed by thin layer chromatography. There is no significant difference between the stimulated rates of P(i) (32) incorporation into phospholipids of the two different microsomal subfractions in response to phenobarbital treatment. The drug-induced enzyme synthesis is unaffected by adrenalectomy.