Down-regulation of the hepatic cytochrome P450 by an acute inflammatory reaction: implication of mediators in human and animal serum and in the liver.
1. 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 (5 ml), and in the serum of humans with an acute upper respiratory tract viral infection. 2. 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 4 h 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 24 h after the injection of turpentine showed the same ability to down-regulate hepatic P450 as the serum obtained at 48 h. 3. The efficacy (Emax) of RS(INFLA) to inhibit the formation of theophylline metabolites differed, i.e. 1,3DMU > 1MU > 3MX, and the potency of serum mediators (IC50) was similar for 3MX and 1MU, but lower for 1,3DMU. 4. 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. 5. 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 (r2= 0.8870) suggesting that lipid peroxidation could directly or indirectly be involved in the P450 down-regulation.
El-Kadi
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AO
Department of Pharmacology, Faculty of Medicine, Université de Montréal, Québec, Canada.
Maurice
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H
Ong
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du Souich
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D000818:Animals; D001711:Biotransformation; D002478:Cells, Cultured; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D015536:Down-Regulation; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood / Q000378:metabolism*; D015227:Lipid Peroxidation; D008099:Liver / Q000201:enzymology*; D008297:Male; D011817:Rabbits; D013806:Theophylline / Q000493:pharmacokinetics; D014777:Virus Diseases / Q000378:metabolism
D018836:Inflammation Mediators; D003577:Cytochrome P-450 Enzyme System; D013806:Theophylline