NITRIC OXIDE-MEDIATED INHIBITION OF CYTOCHROME-P450 BY INTERFERON-GAMMA IN HUMAN HEPATOCYTES

The role of nitric oxide in the inhibition of the cytochrome P450 syst em produced by interferon-gamma in human hepatocytes has been examined . Nitric oxide exogenously released from S-nitroso-N-acetylpenicillami ne produced a dose-dependent decrease in cytochrome P4501A2 activity, assessed as 7-ethoxy resorufin O-deethylation. After 24 hr of treatmen t with 300 U/ml interferon-gamma, 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 hepatocyte s. This inhibition was concentration-dependently prevented by N-G-mono methyl-L-arginine, a competitive inhibitor of nitric oxide biosynthesi s. Comparable results were observed for cytochrome P4502A6 (7-coumarin hydroxylation), 2B6 (7-benzoxyresorufin O-dealkylation) and 3A4 (test osterone 6 beta-hydroxylation) activities. Decreases in CYP1A2 activit y found after exposure of 3-methylcholanthrene-treated hepatocytes to interferon-gamma were also reversed in the presence of N-G-monomethyl- L-arginine. Down-regulation of cytochrome P4501A2 and 3A4 expression b y interferon-gamma was observed in parallel. This study suggests that at least some of the interferon-gamma effects on human hepatocyte cyto chrome P450 isoenzymes are mediated by nitric oxide biosynthesis.