COMPARATIVE STUDY OF INHIBITORY ACTION OF ETHIONINE, 8-AZAGUANINE, 6-MERCAPTOPURINE AND X- OR GAMMA-IRRADIATION ON THE INDUCTION OF THE HEPATIC DRUG-METABOLIZING ENZYMES BY PHENOBARBITAL OR PHENAGLYCODOL

Abstract

Enzyme activities, in liver slices, catabolizing phenobarbital and phenaglycodol were measured before and after treatment of rats with the inhibitors or 750-r, whole-body x irradiation or 700- and 1400-r Co⁶⁰ gamma irradiation. It was shown that 200 mg kg ethionine, which itself does not modify the enzyme activities, completely abolished the induction of the increased enzyme activity by phenobarbita and phenaglycodol, when it was administered 30 min before injection of the inducing drugs. When ethionine was administered 12 hr after the injection of the inducers, its inhibitory action on the induction was decreased about 50%, and ethionine administered 47 hr after phenobarbital was completely ineffective. Results suggest that ethionine inhibits biosynthesis of the apoenzymes, and does not directly affect enzyme activities. On the other hand, 8azaguanine only partly inhibited induction of the enzymes by phenobarbital or phenaglycodol. At doses of more than 125 mg/kg, 8-azaguanine manifests a slight depressor ef fect on activity of the enzymes. 6-Mercaptopurine did not have a significant effect on the induction of the enzymes, and x or gamma irradiation did not affect induction of the enzymes. That ethionine inhibited the induction of increase of pentobarbital and phenaglycodol metabolism indicates that the increased drug-metabolizing enzymes inducedmore » by the administration of these drugs are brought about through the de novo synthesis of enzyine protein. It is suggested that induction of increase of hepatic microsomal druginetabolizing enzymes might be accompanied by de novo biosynthesis of microsomal RNA, and that the RNA present in microsome may be sufficient for stimulation by the inducing drugs to carry out the biosynthesis of the apoenzyme. According to an earlier hypothesis, there are 2 types of inducible enzyines, one is 8-azaguanine-sensitive and the other is 8-azaguanine-resistant and the RNA responsible for biosynthesis of 8-azaguinine-sensitive inducing enzyme is of short active life and that of 8-azaguanine-resistant inducing enzyme is of long active life. According to this hypothesis, the RNA responsible for biosynthesis of the inducing hepatic enzymes may be of long life. The difference in the effectiveness between 8-azaguanine and 6mercaptopurine and radiation is interpreted on the basis of their different actions on RNA biosynthesis. (BBB)« less