Cytochrome P450 inactivation by serum from humans with a viral infection and serum from rabbits with a turpentine-induced inflammation: the role of cytokines.
Serum from humans with an acute upper respiratory viral infection and from rabbits with turpentine-induced inflammation reduce the catalytic activity of hepatic cytochrome P450 (P450). The aim of this study was to identify the serum mediators responsible for the decrease in P450 activity. Rabbit and human sera were fractionated by size exclusion chromatography and the fractions tested for their ability to reduce the activity and amount 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. In rabbit serum, the fraction containing proteins of M(r) 23-15 kDa decreased P450 content by 41%, but did not alter the amount of the apoproteins. Anti-IL-6 antibody added to the M(r) 23-15 kDa fraction restored P450 content to 97% of control values, while anti-IL-1beta, TNF-alpha and IFN-gamma antibodies 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%. In human serum, the fraction containing proteins of M(r) >95 kDa lowered P450 content by 43% without modifying the amounts of CYP1A1/2. Neutralization experiments showed that IFN-gamma, IL-6, and IL-1beta contributed to the decrease in P450 content. In conclusion, the present results demonstrate that IL-6, and IFN-gamma, IL-6 and IL-1beta 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.
Bleau
A M
AM
Department of Pharmacology, Faculty of Medicine, University of Montréal, Montréal, Québec, Canada.
Levitchi
M C
MC
Maurice
H
H
du Souich
P
P
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D000914:Antibodies, Viral / Q000097:blood / Q000276:immunology*; D002478:Cells, Cultured; D005591:Chemical Fractionation; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects* / Q000378:metabolism; D016207:Cytokines / Q000276:immunology / Q000502:physiology; D006801:Humans; D007106:Immune Sera / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology*; D007249:Inflammation / Q000097:blood / Q000139:chemically induced / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology; D007375:Interleukin-1 / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology; D007527:Isoenzymes / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D008297:Male; D011817:Rabbits; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D014425:Turpentine / Q000009:adverse effects*
D000911:Antibodies, Monoclonal; D000914:Antibodies, Viral; D016207:Cytokines; D007106:Immune Sera; D007375:Interleukin-1; D015850:Interleukin-6; D007527:Isoenzymes; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D003577:Cytochrome P-450 Enzyme System; D014425:Turpentine