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.
Donato
M T
MT
Unidad de Hepatología Experimental, Centro de Investigación, HospitalUniversitario La Fe, Valencia, Spain.
Guillén
M I
MI
Jover
R
R
Castell
J V
JV
Gómez-Lechón
M J
MJ
D000328:Adult; D000368:Aged; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D008099:Liver / Q000201:enzymology*; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D019323:omega-N-Methylarginine / Q000494:pharmacology
D065609:Cytochrome P-450 CYP1A2 Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D012333:RNA, Messenger; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D007371:Interferon-gamma; D003577:Cytochrome P-450 Enzyme System