Depression of the hepatic cytochrome P450 by an acute inflammatory reaction: characterization of the nature of mediators in human and rabbit serum, and in the liver.

There is increasing evidence suggesting that several mediators are involved in the cascade of events leading to the depression of the cytochrome P450 (P450) by an inflammatory reaction. The present study aimed to confirm the presence of mediators in the serum (RS(INFLA)) and hepatocytes (H(INFLA)) of rabbits with an acute inflammatory reaction, and in the serum of humans with an acute upper respiratory tract viral infection (HS(URTVI)). The inflammatory reaction was induced by the s.c. injection of 5 ml of turpentine. Incubation of RS(INFLA) or HS(URTVI) with H(INFLA) depressed the P450, diminished the formation of theophylline metabolites (3-methylxanthine, 1-methyluric acid, and 1,3-dimethyluric acid), and increased lipid peroxidation. The addition of preheated RS(INFLA) or HS(URTVI) to H(INFLA) did not diminish the amount of P450 or theophylline metabolites, and prevented the increase in lipid peroxidation. Incubating the filtrate of RS(INFLA) or HS(URTVI) dialyzed through membranes with cut-off of 10, 30, 50 and 100 kd, with H(INFLA) showed that rabbit and human mediators have molecular weights ranging from 10 to 30 kd. Incubation of H(INFLA) with hepatocytes from control rabbits (H(CONT)) did not decrease further the P450. However, when RS(INFLA) was added to co-cultured H(CONT) + H(INFLA), the depression of P450 was 37% greater (p<0.05), and the amount of theophylline metabolites generated was around 30% (p<0.05) smaller than that observed when H(CONT) or H(INFLA) were incubated with RS(INFLA). Based on the present results we may speculate that human and rabbit serum mediators are proteins of molecular weights ranging from 10 to 30 kd, and in addition, primed hepatocytes once exposed to the serum mediators release mediators able to depress the P450 in H(CONT).