270 EFFECT OF ENDOTOXIN ON RAT HEPATIC DRUG METABOLISM DURING DEVELOPMENT

Abstract

The frequency of gram negative infections and endotoxemia in the perinatal period prompted an investigation of the effects of endotoxin (E. coli. 026B6) on hepatic drug metabolism. Chronic dosing of endotoxin (0.2 mg/kg/d × 7 days) to lactating mothers significantly stimulated hepatic microsomal cytochrome P-450 (118%) and aminopyrine demethylase activity (114%). No alteration in neonatal enzyme activities was observed. Body and liver weight ratios or microsomal protein level of mothers and neonates were not altered by chronic administration of endotoxin to mothers during the experimental period. The acute i.p. administration of of endotoxin to mothers (1.4 mg/kg on the 7th day after parturition)significantly decreased the activity of aminopyrine demethylase (48%) and content of cytochrome P-450 (25%). When neonates themselves were injected (i.p.) with endotoxin (1.0 mg/kg) at 7, 16 and 27 days of age, a significant reduction in levels of mixed function oxidase enzymes was observed. Cytochrome P-450 contents were reduced by 57, 32 and 24% and aminopyrine demethylation decreased by 78, 48 and 34% in 7, 16 and 27 day old animals resptively. These observations indicate that the ability of mothers and neonates to metabolize drugs is significantly decreased upon acute exposure to endotoxin and this demands careful evaluation of drug disposition in gram negative sepsis during perinatal period. Supported by NIH Grant HD 10063.