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Vol. 281, Issue 1, 484-490, 1997
in Human Hepatocytes1
Unidad de Hepatología Experimental, Centro de
Investigación, Hospital Universitario La Fe, Valencia, Spain
The role of nitric oxide in the inhibition of the cytochrome P450
system produced by interferon-
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-,
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
6
-hydroxylation) activities. Decreases in CYP1A2 activity found
after exposure of 3-methylcholanthrene-treated hepatocytes to
interferon- were also reversed in the presence of
NG-monomethyl-L-arginine. Down-regulation of
cytochrome P4501A2 and 3A4 expression by interferon- was observed in
parallel. This study suggests that at least some of the interferon-
effects on human hepatocyte cytochrome P450 isoenzymes are mediated by nitric oxide biosynthesis.
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