L-NAME prevents in vivo the inactivation but not the down-regulation of hepatic cytochrome P450 caused by an acute inflammatory reaction.
A turpentine-induced inflammatory reaction (TIIR) down-regulates multiple isoforms of hepatic cytochrome P450 (P450) and increases microsomal lipid peroxidation. Since the synthesis of nitric oxide (NO*) is stimulated by inflammatory reactions, and NO* can depress the P450, it was of interest to investigate in vivo whether L-NAME and theophylline, by its anti-inflammatory properties, could prevent the depression of P450 caused by a TIIR. Control and rabbits with a TIIR received L-NAME for 72 h, and the activity of P450 was assessed in vivo and in vitro. In vivo, TIIR reduced theophylline systemic clearance by 50% (p<0.05), P450 total content by 67%, and the amount of CYP1A1/2 proteins by around 60% (p<0.05). L-NAME partially prevented the decrease in theophylline systemic clearance and in P450 total content, as well as the increase in lipid peroxidation; however, L-NAME did not hinder CYP1A1/2 proteins down-regulation. L-NAME did not modify the in vitro ability of the serum of rabbits with TIIR to decrease P450 activity, suggesting that the effect of L-NAME is not associated to a decrease in serum mediators. As assessed by the concentration in seromucoids, theophylline did not modify the severity of the inflammatory reaction, nor did it prevent the decrease in P450 activity. In conclusion, a TIIR down-regulates and reduces P450 activity, decrease that is at least in part mediated by NO*; theophylline does not prevent TIIR-induced P450 decrease in activity.
Barakat
M M
MM
Department de Pharmacologie, Faculté of Médecine, Université de Montréal, Québec, Canada.
El-Kadi
A O
AO
du Souich
P
P
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D015536:Down-Regulation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology; D007249:Inflammation / Q000139:chemically induced / Q000201:enzymology*; D007509:Irritants; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011817:Rabbits; D013806:Theophylline / Q000494:pharmacology; D014425:Turpentine
D004791:Enzyme Inhibitors; D007509:Irritants; D010726:Phosphodiesterase Inhibitors; D003577:Cytochrome P-450 Enzyme System; D013806:Theophylline; D019331:NG-Nitroarginine Methyl Ester; D014425:Turpentine