Nitric Oxide Inhibits Dioxin Action for the Stimulation of Cyp1a1 Promoter Activity

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Since it is known that hypoxia increases inducible nitric oxide synthase (iNOS) gene expression through the hypoxia responsive element, it was hypothesized that nitric oxide could be a mediator of hypoxia to inhibit Cyp1a1 promoter activity. In order to test this hypothesis, we have undertaken a study to examine the effects of hypoxia and nitric oxide on Cyp1a1 promoter activity in Hepa I cells. Mouse Cyp1a1 5' flanking DNA, 1.6kb, was cloned into pGL3 expression vector in order to construct pmCyp1a1-Luc. Hepa I cells were tranfercted with pmCyp1a1-Luc and were treated with 10^<-9>M 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the presence or absence of various hypoxic agents such as 10^<-6>-10^<-4>M cobalt chloride or 10^<-6>-10^<-4>M picolinic acid or 10^<-6>-10^<-4>M desferrioxamine. The luciferase activity of the reporter gene was measured from pmCyp1a1-Luc transfected Hepa I cell lysate which contains 2μg total protein using luciferin as a substrate. Hypoxic agents such as cobalt chloride, picolinic acid, and desferrioxamine showed inhibition of luciferase activity that was induced by 10^<-9>M TCDD treatment in a dose dependent manner. Concomitant treatment of 1mM N^G-nitro-l-arginine with 10^<-6>-10^<-4>M cobalt chloride or 10^<-6>-10^<-4>M desferrioxamine or 10^<-6>-10^<-4>M picolinic acid or 10^<-6>-10^<-4>M sodium nitroprusside recovered luciferase activity from the TCDD induced luciferase activity that was inhibited by hypoxic agents. These data demonstrated that nitric oxide might be a mediator of iron chelating agents and hypoxic agents to inhibit dioxin induced Cyp1a1 promoter activity in Hepa I cells.
公益社団法人日本薬学会の論文
2000-05-01

Nitric Oxide Inhibits Dioxin Action for the Stimulation of Cyp1a1 Promoter Activity

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