Induction of drug metabolizing enzyme system in the liver

Summary 1. Accelerated drug metabolism in liver cells was discovered during studies of the cause of barbiturate tolerance and of the way in which polycyclic hydrocarbons protect against the actions of several carcinogenic compounds. — 2. It is elicited by many lipid soluble drugs and is accompanied by increased synthesis of haem and enzyme proteins. It is due to increased activity of the drug metabolizing microsomal enzyme-complexes in the liver which consist of non specific mixed function oxidases and various transferases. — 3. Acceleration of drug metabolism is accompanied by hypertrophy of smooth intracellular membranes and enlargement of the liver. It is dependent on the concentration of the inducer in the endoplasmic reticulum and seems to be influenced by the stability of a complex formed between the drug and cytochrome P-450, as well as by certain, as yet unidentified properties possessed by certain types of inducing agents. — 4. In man it has been observed in patients during and after treatment with a few drugs which have a high inducing capacity and are prescribed in large doses. — 5. Accelerated drug metabolism might be highly advantageous and beneficial in protecting an organism against an overload of endogenous or exogenous toxic compounds, but it can also be harmful if it results in increased production of toxic metabolites. — 6. It can be regarded as a hitherto unknown pharmacological effect on the regulation of the synthesis-rate of enzymes involved in drug metabolism.Presented as Feldberg Foundation Lecture 1972 in St. Mary's Hospital Medical School on March 8th, 1972