Role of hydrogen peroxide in hypoxia-induced erythropoietin production

The addition of exogenous H₂O₂ inhibited hypoxia-induced erythropoietin (Epo) production in the human hepatoma cell line HepG2. Likewise, elevation of endogenous H₂O₂ levels by the addition of menadione or the catalase inhibitor, aminotriazole, dose-dependently lowered Epo production. The inhibitory effect of exogenous H₂O₂ on Epo formation could be completely overcome by co-incubation with catalase. When GSH levels in HepG2 cells were lowered, Epo production was more susceptible to H₂O₂-induced inhibition, indicating that H₂O₂ might affect thiol groups in regulatory proteins. Endogenous production of H₂O₂ in HepG2 cells was dependent on the pericellular O₂ tension, being lowest under conditions of hypoxia. Our results support the hypothesis that an H₂O₂-generating haem protein might be part of the O₂ sensor that controls Epo production. High H₂O₂ levels under conditions of normoxia suppress, whereas lower levels in hypoxic cells allow epo gene expression.