Effect of Drugs on the Formation of Smooth Endoplasmic Reticulum and Drug‐metabolizing Enzymes

Abstract

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).

Liver size and indices of drug metabolism in epileptics.

“…Its content has been shown to rise and fall paralle with changes in drug metabolism in animals (Remmer & Merker, 1965). P450 levels have been increased in the livers of patients on short-term (Billing & Black, 1971) and chronic (Remmer, Schoene, Fleischman & Held, 1973) use of anticonvulsants.…”

Relation between cytochrome P-450 increase and endoplasmic reticulum proliferation in hepatocytes of mice treated with phenobarbital: a microphotometric and morphometric study.

“…Phenobarbital (PB) administration to animals induces a marked increase in the amount of cytochrome P-450 (P-450) in the liver (1,3,9,15,17) and prominent proliferation of the endoplasmic reticulum (ER) in hepatocytes (12,16,18,19,21). Although the increase in P-450 after PB administration is considered to relate to the ER proliferation (19), no simple relationship is apparent between P-450 induction and ER proliferation (3).…”

“…Although the increase in P-450 after PB administration is considered to relate to the ER proliferation (19), no simple relationship is apparent between P-450 induction and ER proliferation (3).…”

Further study of α benzene hexachloride inhibition of aflatoxin B1 hepatocarcinogenesis in rats

“…This was similar to the effect of dichlorodiphenyl trichloroethane (DDT) on rat liver (Ortega, 1966 (Schulte-Hermann et al, 1968). BHC and phenobarbitone have also been found to induce smooth endoplasmic reticulum (SER) proliferation and microsomal drug metabolizing enzymes of the liver (Koransky et al, 1-964;Remmer & Merker, 1965;Thamavit et al, 1974 (Swenson et al, 1971;Garner, 1975;Moule et al, 1975). Thus, the increase in the rate of AFB detoxification and the reduction in nucleicacid binding (probably due to competitive inhibition) may account for the protective effects of BHC on aflatoxin carcinogenesis.…”