THE EFFECT OF PHENOBARBITAL ON DRUG METABOLIC ENZYME ACTIVITY, ULTRASTRUCTURE AND GROWTH OF A "MINIMAL DEVIATION" HEPATOMA (MORRIS 7800)

¹ Department of Pharmacology, College of Medicine, University of Iowa, Iowa City, Iowa, and National Cancer Institute, National Institutes of Health, Bethesda, Maryland

The drug metabolic enzyme pattern and the ultrastructure of a "minimal deviation" hepatoma (Morris 7800) were studied before and after phenobarbital treatment of animals bearing these tumors. The control hepatoma cytoplasm contained an extensively developed endoplasmic reticulum. However, the prominent, parallel stacks of flattened, rough-surfaced endoplasmic reticulum cisternae, characteristic of liver parenchymal cells, were absent in the hepatoma. The smooth-surfaced endoplasmic reticulum was relatively abundant in the hepatoma and was even more easily visualized than in normal liver because of the absence of large numbers of densely staining glycogen granules. The Morris 7800 hepatoma microsomal enzymes metabolized a wide variety of chemical substrates even before phenobarbital treatment of animals bearing these tumors. Kinetic studies demonstrated similar apparent Michaelis constants (K_m) and estimated maximal enzyme reaction velocities (V_max) for benzpyrene and aniline hydroxylation in the hepatoma and rat liver. The apparent K_m value for the side chain oxidation of hexobarbital was the same for the hepatoma and rat liver. However, the estimated V_max for the metabolism of hexobarbital was greatly reduced in the hepatoma as compared with liver. Acute phenobarbital administration caused some perinuclear increase in small tubular, smooth-surfaced endoplasmic reticulum (SER) in the hepatoma, and an extensive increase in the perinuclear small tubular type of SERl in the live-parenchymal cells. This phenobarbital-induced increase in SER membranes was accompanied by an increase in the ability of both liver and tumor to metabolize hexobarbital. Chronic phenobarbital administration caused extensive proliferation of the SER and increases in the rate of side chain oxidation of hexobarbitai in both liver and hepatoma. The form of the SER of the liver or hepatoma after long-term phenobarbital administration was an irregularly dilated type of type in contrast to the small tubules seen after acute exposures to phenobarbital. Rats bearing Morris 7800 hepatoma had normal levels of the microsomal drug-metabolizing enzymes in their liver. The presence of nonnecrotic tumor tissue, therefore, did not appear to affect drug metabolism in the host liver. Host-liver drug metabolic enzyme activity was affected just before the animal was killed by the tumor, but this was believed to be a nonspecific effect which can be mimicked by any near fatal disease state or by severe starvation.