Cytochrome P450 inactivation by serum from humans with a viral infection and serum from rabbits with a turpentine-induced inflammation: the role of cytokines

1 Serum from humans with an acute upper respiratory viral infection and fro m rabbits with turpentine-induced inflammation reduce the catalytic activit y of hepatic cytochrome P450 (P450). The aim of this study was to identify the serum mediators responsible for the decrease in P450 activity. 2 Rabbit and human sera were fractionated by size exclusion chromatography and the fractions tested for their ability to reduce the activity and amoun t of P450 after 4 h of incubation with hepatocytes from turpentine-treated rabbits (H-INF) Rabbit and human sera decreased P450 activity by around 40% without any change in the amount of CYP1A1 and 1A2 apoproteins. 3 In rabbit serum, the fraction containing proteins of M-r 23-15 kDa decrea sed P450 content by 41%, but did not alter the amount of the apoproteins. A nti-IL-6 antibody added to the M-r 23-15 kDa fraction restored P450 content to 97% of control values, while anti-IL-1 beta, TNF-alpha and IFN-gamma an tibodies had no effect. Supporting the role of IL-6, incubation of H-INF in the presence of IL-6 for 4 h reduced P450 content by 40%. 4 In human serum, the fraction containing proteins of M-r > 95 kDa lowered P450 content by 43% without modifying the amounts of CYP1A1/2. Neutralizati on experiments showed that IFN-gamma, IL-6, and IL-1 beta contributed to th e decrease in P450 content. 5 In conclusion, the present results demonstrate that IL-6, and IFN-gamma, IL-6 and IL-1 beta are the serum mediators released in vivo by a turpentine -induced inflammatory reaction in the rabbit and an upper respiratory viral infection in humans, respectively, inactivating hepatic P450.