[Heme as a signaling molecule under environmental stress]

One of the most remarkable revolutions during the history of animal kingdom is the adaptation to oxygen, a highly toxic gas produced by plants. Based on the high affinity of heme toward oxygen, it has been believed that heme itself and/or hemoprotein should play significant roles in the processes of adaptation. Recently, two novel functions of heme and its metabolites were identified; namely, hemoprotein is an oxygen sensor and biliverdin and bilirubin, catabolites of heme, are antioxidants. Thus, heme is a key molecule in the responses to environmental stress, including oxygen. Although activation of hypoxia inducible factor-1, which induces expression of genes encoding erythropoietin and heme oxygenase (HO-1), is generally accepted to be controlled by oxygen sensor, the precise signaling pathway has not yet been well elucidated. Various stresses such as hypoxia are known to activate the HO-1 gene, the key enzyme of heme degradation, resulting in the marked conversion of pro-oxidant (heme) into its antioxidative catabolites. The induction is, therefore, supposed to have protective effects. Recent reports on HO-1 deficiency also support this hypothesis that the activation of the HO-1 gene is one of the most important defense mechanisms against environmental stress.