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The cellular changes which lead to the increase of drug-metabolizing enzymes following drug administration are explained by correlating new biochemical data with previously reported electron microscopic and pharmacologic observations. Repeated administration of phenobarbital and several other drugs results in a quantitative increase of the smooth endoplasmic reticulum of the liver cell. The marked increase in drug-metabolizing enzymes is found to occur in this enlarged smooth membrane fraction of the endoplasmic reticulum.

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Various lipid soluble drugs act unspecifically on the endoplasmic reticulum of liver cells. They cause the development of new smooth membranes containing drug metabolizing enzymes.1.2 A report about this phenomenon should begin by illustrating the alteration in the image of the liver cells after treating animals with a number of unrelated drugs. In connection with the morphological description I shall attempt to show that the interpretation of the changes observed with the electron microscope correspond with results obtained with biochemical methods. Afterwards, evidence will be given for a typical enzyme induction, i.e., the enhanced synthesis of a particular microsonial cytochrome which proceeds the new formation of intracellular membranes. Finally we should think over the consequences of this peculiar side effect which should be taken into consideration in drug therapy and in evaluation of chronic toxicity studies. Morphological A Iterations in the Endoplasmic Reticulum of Liver Cells after Treatment with Various DrugsThe structures of normal liver cells which can be observed under the electron microscope are diagrammed in FIGURE 1. Besides the nucleus and mitochondria the endoplasmic reticulum (e.r.) is clearly visible. It consists mainly of two different types of membranes, the smooth and the rough.3 The latter are encrusted with small particles, the ribosomes. Moreover the cytoplasm is filled with dense granules which can be demonstrated after fixation with lead hydroxide. The nature and function of these particles are unknown (FIGURE 2). After treating rats and rahbits with several injections of 50-100 mg./kg. of three different and unrelated drugs such as phenobarbital, tolbutamide, or nikethamide, striking changes in the image of e x . are observed. The dense granules in the cytoplasma are replaced by numerous new smooth membranes which form a clearly visible tridimensional lattice work of tubules about 25-50 mp, in diameter bordered by membranes 6 m p thick (FIGURE 3 ) . However nucleus, mitochondria and the rough membranes of the ex. appear to remain unchanged, but the number of free ribosomes not associated with rough membranes is increased. The development of new smooth membranes is even detectable after the first injection of phenobarbital and achieved its maximum after the fifth dose given daily or on alternating days.Porter and Bruni4 observed a similar increase of smooth membranes after treating rats with the carcinogenic 3'-methyl-p-dimthylaminoazobenzol. However the appearance of new smooth membranes was followed by disorganization of rough membranes. Changes in the composition and in the Content of Enzymes in the Endoplastnic ReticulumIn order to elucidate the morphological alterations in the liver cells we isolated the ex., which, as it is well known, desintegrates to microsomes when liver tissue FIGURE 1. Diagram of the normal liver cell of rats. FIGURE 2. Electron micrograph of a normal rat liver cell. 0 rat, 60 g. of weight . ( 1 : 21,000).

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