Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.14.16.2 (tyrosine hydroxylase)
 14,760 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the current study, we investigated links between O2-regulated H2O2 formation and the hypoxic induction of mRNA for tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine synthesis, in O2-sensitive PC-12 cells. During exposure of PC-12 cells to 5% O2, H2O2 concentration decreased by 40% as measured with 2',7'-dichlorofluorescein (DCF). Treatment with H2O2 reduced TH mRNA during normoxia and prevented the induction of TH mRNA during hypoxia. Treatment with catalase or N-(2-mercaptopropionyl)-glycine, a reducing antioxidant agent that decreases H2O2 concentration, also induced TH mRNA. Deferoxamine (DF), an iron chelator, failed to affect H2O2 formation but induced TH mRNA in normoxia and hypoxia. CoCl2 led to a decrease in H2O2 at 20 h of treatment but induced TH mRNA during normoxia and hypoxia before it affected H2O2. In conclusion, TH gene expression correlates inversely with H2O2 formation. DF and CO2+ seem to affect TH gene expression in the mechanism downstream from the H2O2 formation rather than by interfering with the H2O2-generating activity of the O2 sensor.
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PMID:Role of H2O2 and heme-containing O2 sensors in hypoxic regulation of tyrosine hydroxylase gene expression. 945 25

The transcription factor hypoxia-inducible factor (HIF) is essential for the activation of several genes that promote the survival of cells exposed to oxidative stress. Expression of tyrosine hydroxylase (TH), which is the rate-limiting enzyme in the dopamine (DA) synthesis, is one of the genes that are positively regulated by HIF. Accordingly, HIF induction results in elevated DA release in various cell lines in vitro. HIF prolyl hydroxylase (HPH) is critically involved in the negative regulation of HIF levels. We investigated the in vivo effects of the HPH inhibitor FG0041 on brain DA function in rats by microdialysis in freely moving rats, locomotor activity, and Western blot analysis. Administration of FG0041 (10 mg/kg i.p.), as an acute (single injection), or as subchronic (once daily for 6 days) treatment and cobalt chloride (CoCl2) (60 mg/kg s.c.) potentiated potassium (K+) induced increases in extracellular levels of DA levels in the rat striatum. The increase in extracellular DA of freely moving rats was sought in relationship to locomotor activity in rats. A significant increase in locomotor activity was observed in FG0041-treated rats compared with vehicle on a cocaine challenge. In support of these findings, protein levels of TH in the rat brain stem were increased after treatment with FG0041. These data indicate that FG0041 augments DA function in the rat brain. Inhibition of HPH enhances DA function by increasing DA release, which has implications for the use of HIF induction in the treatment of neurodegenerative diseases.
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PMID:HIF prolyl hydroxylase inhibition augments dopamine release in the rat brain in vivo. 1915 59