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Down‐regulation of the hepatic cytochrome P450 by an acute inflammatory reaction: implication of mediators in human and animal serum and in the liver
Author(s) -
ElKadi Ayman O S,
Maurice Hélène,
Ong Huy,
Souich Patrick
Publication year - 1997
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0701232
Subject(s) - medicine , endocrinology , cytochrome p450 , lipid peroxidation , incubation , theophylline , inflammation , chemistry , biology , metabolism , biochemistry , oxidative stress
Infection and inflammation trigger a cascade of mediators that eventually will down‐regulate the hepatic cytochrome P450 (P450). The present study aimed to characterize the mediators contained in the serum of rabbits with an acute inflammatory reaction (AIR) induced by the s.c. injection of turpentine (5ml), and in the serum of humans with an acute upper respiratory tract viral infection. Hepatocytes from control (H CONT ) rabbits and rabbits with an AIR (H INFLA ) were isolated and cultured. Compared with H CONT in H INFLA the production of theophylline metabolites, 3‐methylxanthine (3MX), 1‐methyluric acid (1MU), and 1,3‐dimethyluric acid (1,3DMU) was reduced as was the amount of total P450, while lipid peroxidation was increased. Incubation of H INFLA with serum of rabbits with an AIR (RS INFLA ) for 4h further reduced the formation of the metabolites of theophylline as well as the amount of P450, and enhanced the lipid peroxidation. RS INFLA obtained 6, 12 and 24h after the injection of turpentine showed the same ability to down‐regulate hepatic P450 as the serum obtained at 48h. The efficacy (E max ) of RS INFLA to inhibit the formation of theophylline metabolites differed, i.e. 1,3DMU>1MU>3MX, and the potency of serum mediators (IC 50 ) was similar for 3MX and 1MU, but lower for 1,3DMU. Incubation of serum of human volunteers (HS INFLA ) with a viral infection with H CONT or H INFLA reduced the production of theophylline metabolites, as well as the amount of P450, and increased the lipid peroxidation. HS INFLA depressed 1,3DMU more efficiently than 3MX and 1MU. HS INFLA reduced 3MX with greater efficacy than did RS INFLA . Potency was very variable but not different from rabbits. It is concluded that the serum of rabbits with an AIR or of humans with a viral infection contain several mediators that inhibit noncompetitively various isoenzymes of the hepatic P450. The decrease in P450 induced by HS INFLA or RS INFLA is closely associated with the increase in lipid peroxidation ( r 2 =0.8870) suggesting that lipid peroxidation could directly or indirectly be involved in the P450 down‐regulation.