Nitric oxide affects the production of reactive oxygen species in hepatoma cells: implications for the process of oxygen sensing.

Abstract	Treatment of human hepatoma cells (HepG2) with NO-donors for 24 h inhibited hypoxia-induced erythropoietin (EPO) gene activation. NO was found to increase the production of reactive oxygen species (ROS), the putative signaling molecules between a cellular O2-sensor and hypoxia inducible factor 1 (HIF-1). HIF-1 is the prime regulator of O2-dependent genes such as EPO. NO-treatment for more than 20 h reduced HIF-1-driven reporter gene activity. In contrast, immediately after the addition of NO, ROS levels in HepG2 cells decreased below control values for as long as 4 h. Corresponding to these lowered ROS-levels, HIF-1 reporter gene activity and EPO gene expression transiently increased but were reduced when ROS levels rose thereafter. Our findings of a bimodal effect of NO on ROS production shed new light on the involvement of ROS in the mechanism of O2-sensing and may explain earlier conflicting data about the effect of NO on O2-dependent gene expression.
Authors	J Genius, J Fandrey
Journal	Free radical biology & medicine (Free Radic Biol Med) Vol. 29 Issue 6 Pg. 515-21 (Sep 15 2000) ISSN: 0891-5849 [Print] United States
PMID	11025195 (Publication Type: Journal Article)
Chemical References	Acridines DNA-Binding Proteins HIF1A protein, human Hypoxia-Inducible Factor 1 Hypoxia-Inducible Factor 1, alpha Subunit Nitric Oxide Donors Nitrogen Oxides Nuclear Proteins Onium Compounds RNA, Messenger Reactive Oxygen Species S-nitro-N-acetylpenicillamine Transcription Factors Erythropoietin spermine nitric oxide complex 10,10'-dimethyl-9,9'-biacridinium Spermine Nitric Oxide diphenyleneiodonium Hydrogen Peroxide NADH, NADPH Oxidoreductases NADPH Oxidases Penicillamine Oxygen
Topics	Acridines (metabolism) Anaerobiosis Carcinoma, Hepatocellular (enzymology, metabolism, pathology) DNA-Binding Proteins (genetics) Erythropoietin (analysis, genetics) Gene Expression Regulation, Neoplastic (drug effects) Genes, Reporter Humans Hydrogen Peroxide (metabolism) Hypoxia-Inducible Factor 1 Hypoxia-Inducible Factor 1, alpha Subunit NADH, NADPH Oxidoreductases (metabolism) NADPH Oxidases Nitric Oxide (metabolism) Nitric Oxide Donors (pharmacology) Nitrogen Oxides Nuclear Proteins (genetics) Onium Compounds (pharmacology) Oxygen (metabolism) Penicillamine (analogs & derivatives, pharmacology) RNA, Messenger (genetics, metabolism) Reactive Oxygen Species (metabolism) Signal Transduction Spermine (analogs & derivatives, pharmacology) Transcription Factors Transcriptional Activation Transfection Tumor Cells, Cultured

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