Inhibition of hepatic drug metabolism in the rat after Corynebacterium parvum treatment

Abstract

Drug-metabolizing enzyme activities, cytochrome concentration, and protein content of hepatic microsomal preparations from adult, female Sprague-Dawley rats were examined at 1-, 3-, 6-, 10-, 14- and 17-day intervals after administration of a single intravenous injection of Corynebacterium parvum ( C. parvum) at a dose of 10 mg/m 2. Aniline hydroxylase (AH) activity, aminopyrine demethylase (APD) activity, and cytochrome P-450 concentration were reduced 20–50% on days 3–6 and, thereafter, gradually recovered to control levels by day 17. Cytochrome c reductase activity and cytochrome b 5 concentration were reduced significantly (24%) only on day 10. Microsomal protein concentration was unchanged. C. parvum added in vitro had no effect on AH or APD activity. Although livers of treated rats were only slightly (< 20%) enlarged, gross splenomegaly was apparent, reaching a maximum on day 6. A marked inverse correlation existed between the temporal variation in the size of the spleen and APD activity. In rats killed 6 days after administration of C. parvum at 0.67 to 10.00 mg/m 2, a direct relationship was apparent between the adjuvant dose and the magnitude of reduction of APD activity. A similar relationship was apparent between splenomegaly and APD activity. Histopathologic examination of liver sections from treated rats revealed numerous granulomas throughout the parenchyma. The magnitude of enzyme inhibition generally paralleled the severity of the hepatic lesions.