ROLE OF H2O2 AND HEME-CONTAINING O-2 SENSORS IN HYPOXIC REGULATION OFTYROSINE-HYDROXYLASE GENE-EXPRESSION

In the current study, we investigated links between O-2-regulated H2O2 formation and the hypoxic induction of mRNA for tyrosine hydroxylase (TK), the rate-limiting enzyme in catecholamine synthesis, in O-2-sens itive PC-12 cells. During exposure of PC-12 cells to 5% O-2, H2O2 conc entration decreased by 40% as measured with 2',7'-dichlorofluorescein (DCF). Treatment with H2O2 reduced TH mRNA during normoxia and prevent ed the induction of TH mRNA during hypoxia. Treatment with catalase or N-(2-mercaptopropionyl)-glycine, a reducing antioxidant agent that de creases H2O2 concentration, also induced TH mRNA. Deferoxamine (DF), a n iron chelator, failed to affect H2O2 formation but induced TH mRNA i n normoxia and hypoxia. CoCl2 led to a decrease in H2O2 at 20 h of tre atment but induced TH mRNA during normoxia and hypoxia before it affec ted H2O2. In conclusion, TH gene expression correlates inversely with H2O2 formation. DF and Co2+ Seem to affect TH gene expression in the m echanism downstream from the H2O2 formation rather than by interfering with the H2O2-generating activity of the O-2 sensor.