Cytochrome P450 down-regulation by serum from humans with a viral infection and from rabbits with an inflammatory reaction

Serum from humans with an upper respiratory viral infection (HSURVI) and fr om rabbits with a turpentine-induced acute inflammatory reaction (RSTIAR) r educes the activity of hepatic cytochrome P450 (P450) following 4 h of incu bation. The aim of the present study was to assess the effect of HSURVI and RSTIAR on P450 activity and expression following 24 h of incubation with h epatocytes from control (H-CONT) and rabbits with a TIAR (H-INFLA). RSTIAR incubated with H-CONT for 24 h reduced P450 content and activity, and CYP3A 6 by 45%, without changing CYP1A1 and 1A2; when incubated with H-INFLA, RST IAR decreased P450 content and activity without affecting CYP1A1 or 1A2. HS URVI incubated for 4 h with H-CONT decreased P450 activity without affectin g the amounts of CYP1A1, 1A2, or 3A6, although when incubated for 24 h, P45 0 activity and CYP3A6 amount decreased; HSURVI incubated with H-INFLA for 4 h reduced P450 content and activity, and incubated for 24 h reduced activi ty, P450 content, and amount of CYP1A1 and 1A2 proteins. The present study demonstrates that 1)the effect of RSTIAR and HSURVI depends upon the suscep tibility of the hepatocyte, i.e., H-CONT or primed H-INFLA; 2) P450 down-re gulation is preceded by a decrease in P450 activity; 3) the nature of the i nflammatory reaction determines the repercussions on P450 activity and expr ession; and 4) CYP3A6 is more vulnerable than CYP1A1 and 1A2 to the down-re gulation provoked by an inflammatory challenge.