losartan-potassium and diphenyliodonium

Diphenylene iodonium chloride suppresses the cobaltous chloride-induced expression of erythropoietin by Hep3B cells to about 50% at a concentration of 30 nM. At that concentration, it has no effect on the response to low oxygen. The related compound iodonium diphenyl chloride acts similarly but is a much less effective inhibitor. If, as reported, diphenylene iodonium chloride is a specific inhibitor of cytochrome b, it follows that the response to CoCl2 is dependent on that enzyme but the response to hypoxia is not.

Topics: Biphenyl Compounds; Cobalt; Erythropoietin; Onium Compounds; Tumor Cells, Cultured

Recent studies on the induction of erythropoietin gene expression by hypoxia have indicated that erythropoietin forms part of a widely operative system of gene regulation by oxygen. Similar responses to hypoxia, cobaltous ions and desferrioxamine have indicated that the action of these agents is closely connected with the mechanism of oxygen sensing. To consider further the mechanisms underlying these responses, the effect of iodonium compounds was tested on five genes which show oxygen-regulated expression; erythropoietin, vascular endothelial growth factor (VEGF), lactate dehydrogenase-A (LDH-A), glucose transporter-1 (GLUT-1) and placental growth factor (PLGF). In each case, the response to hypoxia was specifically inhibited by low doses of diphenylene iodonium (Ph1I+). This occurred irrespective of whether the hypoxic response was induction of gene expression (erythropoietin, vascular endothelial growth factor, lactate dehydrogenase-A, glucose transporter-1) or inhibition of gene expression (PLGF). In contrast, the induction of gene expression by cobaltous ions or desferrioxamine was not inhibited by Ph2I+. The differential action of Ph2I+ on the response to hypoxia versus the response to cobaltous ions or desferrioxamine must reflect a difference in the mechanism of action of these stimuli, which will require accommodation in any model of the oxygen-sensing mechanism. Based on the known properties of Ph2I+, the implication of these findings is that the mechanism of oxygen sensing most probably involves the operation of a flavoprotein oxidoreductase.

Topics: Base Sequence; Biphenyl Compounds; Cobalt; Deferoxamine; DNA-Binding Proteins; Enhancer Elements, Genetic; Erythropoietin; Gene Expression; Humans; Hypoxia; Hypoxia-Inducible Factor 1; Hypoxia-Inducible Factor 1, alpha Subunit; Molecular Sequence Data; Nuclear Proteins; Oligodeoxyribonucleotides; Onium Compounds; Oxygen; Transcription Factors; Tumor Cells, Cultured