@article {El-Kadi1112, author = {Ayman O. S. El-Kadi and Anne-Marie Bleau and Isabelle Dumont and H{\'e}l{\`e}ne Maurice and Patrick du Souich}, title = {Role of Reactive Oxygen Intermediates in the Decrease of Hepatic Cytochrome P450 Activity by Serum of Humans and Rabbits with an Acute Inflammatory Reaction}, volume = {28}, number = {9}, pages = {1112--1120}, year = {2000}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Serum of rabbits with a turpentine-induced acute inflammatory reaction (RSINFLA) and serum of humans with a viral infection (HSINF) were previously shown to diminish hepatic cytochrome P450 (P450) content and activity. To document the role of reactive oxygen intermediates in the serum-mediated decrease in P450 content and activity, hepatocytes of rabbits with an acute inflammatory reaction (HINFLA) were incubated with RSINFLAand HSINF for 4 h, and total P450 content (spectrally measurable P450), P450 activity (assessed by estimating the formation of theophylline metabolites), and amount of CYP1A1, CYP1A2, and CYP3A6 proteins were measured. RSINFLA or HSINFdecreased P450 content and activity without affecting the amount of CYP1A1 and -1A2 HINFLA. Exposure of HCONT or HINFLA to hydrogen peroxide (0.01{\textendash}1.0 mM) and sodium nitroprusside (0.01{\textendash}1.0 mM) produced a dose-dependent decrease in P450 content and in the formation of theophylline metabolites without modifying the amount of CYP1A1 and CYP1A2, whereas lipid peroxidation increased. Incubation of l-NAME (0.05{\textendash}1.0 mM), dimethylthiourea (6.25{\textendash}50 mM), or N-acetylcysteine (0.01{\textendash}1.0 mM) with HINFLA partially prevented the decrease in P450 content and activity and the increased lipid peroxidation induced by RSINFLA and HSINF. On the other hand, 3-amino-1,2,4-triazole (10{\textendash}100 mM) or diethyldithiocarbamate (1.0{\textendash}10 mM) potentiated RSINFLA- and HSINF-mediated decreases in P450 content and activity and the increase in lipid peroxidation, without affecting the amount of CYP1A1 or -1A2;dl-buthionine-(S,R)-sulfoximine (2.5{\textendash}25 mM) potentiated only the inhibition of 1,3-dimethyluric acid formation. It is concluded that reactive oxygen intermediates are implicated in the decrease of HINFLA P450 content and activity induced by 4 h of exposure to RSINFLA or HSINF. The American Society for Pharmacology and Experimental Therapeutics}, issn = {0090-9556}, URL = {https://dmd.aspetjournals.org/content/28/9/1112}, eprint = {https://dmd.aspetjournals.org/content/28/9/1112.full.pdf}, journal = {Drug Metabolism and Disposition} }