The microsomal enzyme heme oxygenase 1 catalyzes the first and rate-limiting step of heme degradation producing carbon monoxide (CO), Fe 2+ and biliverdin. We showed that in hepatocytes HO-1 expression is induced in response to its substrate heme, arsenite and by the second messengers cAMP and cGMP. The transcriptional activation of HO-1 and other genes is mediated by a network of signaling pathways, mostly by modulation of the activities of transcription factors and target gene expression. A central position in the signaling cascades regulating a number of cellular processes such as cell growth, differentiation, stress responses and apoptosis occupy mitogen-activated protein kinases (MAPKs). Since MAPKs are involved in stress signaling we investigated the role of arsenite and MAPKs for HO-1 gene regulation in primary rat hepatocytes. We found that the JNK and the p38 MAPK pathways were involved in the sodium arsenite-mediated induction of HO-1 expression. Thereby, the CRE/AP-1 element in the rat HO-1 promoter mediates induction via JNK/c-Jun while p38 isoforms acted differently via an E-box. These investigations will be continued with more detailed experiments on the role of the signalling pathways with the recruitment of various transcription factors.

Fig. 4 Signaling pathways of hepatic heme oxygenase-1 gene regulation. HO-1 gene transcription is induced by various stress stimuli and by 'nonstressful' stimuli, eg. stimuli not associated with oxidant stress. The induction of the HO-1 gene decreases the cellular content of the prooxidants heme and iron and increases the cellular content of the antioxidant bilirubin. MAPK, mitogen-activated protein kinase; PKA, cAMP-dependent protein kinase; PKG, cGMP-dependent protein kinase; ANP, atrial natriuretic peptide