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 (RSINFLA) 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 (HSURTVI) The inflammatory reaction was induced by the s.c. injection of 5 ml of turpentine. Incubation of RSINFLA or HSURTVI 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 RSINFLA or HSURTVI to H-INFLA did not diminish the amount of P450 or theophylline metabolites, and prevented the increase in lipid peroxidation. Incubating the filtrate of RSINFLA or HSURTVI 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 RSINFLA 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 RSINFLA 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.