Role of mononuclear phagocytes in decreased hepatic drug metabolism following administration of Corynebacterium parvum

Abstract

Administration of BCG, Corynebacterium parvum and a number of chemical immunostimulants is known to cause marked decreases in hepatic microsomal drug metabolizing enzyme activity. In this study we found that the per cent inhibition of drug metabolism 7 days following C. parvum vaccine (350 μg per mouse i.p.) was related directly to the extent of splenomegaly. Prior splenectomy, or whole body irradiation, performed concurrently or 2 h after administration of C. parvum prevented the decrease in microsomal enzyme activity. Silica and carrageenan, which are known to lyse macrophages, also blocked the C. parvum effect on drug metabolism, but only if injected 2 h prior to C. parvum administration. A strain of C. parvum with little antitumor activity produced slight splenomegaly and elevation of serum LDH, but drug metabolizing enzyme activity and cytochrome P-450 content remained normal. Characteristic focal intrahepatic inflammatory lesions, consisting principally of macrophages and lymphocytes with adjacent necrotic hepatocytes, were found in splenectomized mice with normal levels of microsomal enzyme activity and cytochrome P-450. However the number and severity of inflammatory lesions generally were related to these parameters and to serum transaminase levels. These results define a role for the reticuloendothelial system in the depression of drug metabolism found after administration of C. parvum.