RT Journal Article
SR Electronic
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
FD American Society for Pharmacology and Experimental Therapeutics
SP 484
OP 490
VO 281
IS 1
A1 M. Teresa Donato
A1 M. Isabel Guillén
A1 Ramiro Jover
A1 José V. Castell
A1 M. José Gómez-Lechón
YR 1997
UL http://jpet.aspetjournals.org/content/281/1/484.abstract
AB 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