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 system produced by interferon-gamma 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-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 hepatocytes. This inhibition was concentration-dependently prevented by N(G)-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 6beta-hydroxylation) activities. Decreases in CYP1A2 activity 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 by interferon-gamma was observed in parallel. This study suggests that at least some of the interferon-gamma effects on human hepatocyte cytochrome P450 isoenzymes are mediated by nitric oxide biosynthesis.