TY - JOUR T1 - Nitric Oxide-Mediated Inhibition of Cytochrome P450 by Interferon-γ in Human Hepatocytes JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 484 LP - 490 VL - 281 IS - 1 AU - M. Teresa Donato AU - M. Isabel Guillén AU - Ramiro Jover AU - José V. Castell AU - M. José Gómez-Lechón Y1 - 1997/04/01 UR - http://jpet.aspetjournals.org/content/281/1/484.abstract N2 - The role of nitric oxide in the inhibition of the cytochrome P450 system produced by interferon-γ in human hepatocytes has been examined. Nitric oxide exogenously released from S-nitroso-N-acetylpenicillamine produced a dose-dependent decrease in cytochrome P4501A2 activity, assessed as 7-ethoxy resorufin O-deethylation. After 24 hr of treatment with 300 U/ml interferon-γ, a rise in nitric oxide release (200% over control cells) and a parallel inhibition in 7-ethoxyresorufin O-deethylase activity (50% of control) were observed in human hepatocytes. This inhibition was concentration-dependently prevented by NG-monomethyl-l-arginine, a competitive inhibitor of nitric oxide biosynthesis. Comparable results were observed for cytochrome P4502A6 (7-coumarin hydroxylation), 2B6 (7-benzoxyresorufin O-dealkylation) and 3A4 (testosterone 6β-hydroxylation) activities. Decreases in CYP1A2 activity found after exposure of 3-methylcholanthrene-treated hepatocytes to interferon-γ were also reversed in the presence of NG-monomethyl-l-arginine. Down-regulation of cytochrome P4501A2 and 3A4 expression by interferon-γ was observed in parallel. This study suggests that at least some of the interferon-γ effects on human hepatocyte cytochrome P450 isoenzymes are mediated by nitric oxide biosynthesis. The American Society for Pharmacology and Experimental Therapeutics ER -