Continued Studies on the Effect of Interferon Inducers on the Hepatic Microsomal Mixed-Function Oxidase System of Rats and Mice

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Abstract
Recently, a number of bacterial preparations, known to induce interferon (IFN), have been shown to decrease the activity of the hepatic mixed-function oxidase system involved in the metabolism of numerous therapeutic agents, as well as certain endogenous agents, such as steroids and prostaglandins. Included among these agents are C. parvum, B. pertussis, endotoxin, and various mycobacteria, e.g., M. bovis and BCG. It has recently been recognized that N-acetylmuramyl-L-alanine-D-isoglutamine (MDP) is the smallest peptidoglycan fragment of the bacterial cell wall that retains many of the biological activities, including induction of interferon. The present study has examined whether injection of MDP into rats and mice would cause a decrease in the activity of the hepatic drugmetabolizing enzyme system. MDP was administered by ip injection in doses of 1, 10, and 100 mg/kg. Animals were sacrificed 24 h after the injection. In rats, injection of MDP caused a dose-dependent decrease in aniline hydroxylase activity, ethylmorphine N—demethylase activity, 7-ethoxycoumarin 0-deethylase activity, and in the level of cytochrome P-450. In mice, aniline hydroxylase activity was unaffected by the lower doses, but was decreased by 100 mg/kg. On the other hand, 7-ethoxycoumarin 0-deethylase activity was decreased in the mouse by both 1 mg/kg and 10 mg/kg doses of MDP. Cytochrome P-450 was decreased only by the two higher doses. Maximal decrease following a single injection of 10 mg/kg MDP to mice occurred at 24 h after injection, but 0-deethylase activity was significantly less than control values for up to 10 days. The effect of multiple injections of MDP was also studied. Injection of a daily dose of 10 mg/kg for three days caused a decrease in 7-ethoxycoumarin 0-deethylase activity similar to that seen after a single injection. Cytochrome P-450 levels were unchanged. The results are interpreted to indicate that MDP does alter the activity of the hepatic drug-metabolizing enzyme system, but the effect is dependent upon the species used and the dose and dosage schedule. Further studies are warranted to see if these effects of MDP relate to induced IFN levels or to other activities of this immunoactive cell wall fragment.

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