The heme oxygenase dilemma in cellular homeostasis: new insights for the feedback regulation of heme catabolism.

Heme must be synthesized and degraded within an individual nucleated cell. Heme degradation is catalyzed by the two isozymes of heme oxygenase, heme oxygenase-1 (HO-1) and HO-2, eventually yielding biliverdin/bilirubin, CO, and iron. These products possess important physiological roles but are potentially toxic to cells. Characteristically, human HO-1 contains no Cys residues, whereas HO-2 contains the potential heme-binding motifs of the Cys-Pro dipeptide. Expression of HO-1 is inducible or repressible, depending on cell types or cellular microenvironments, but expression levels of HO-2 are fairly constant. Thus, the main regulation of heme catabolism is a problem of the balance between induction and repression of HO-1. Notably, HO-1 expression is induced by heme in all mammalian cells examined, but is repressed by hypoxia in certain types of cultured human cells. The recent discovery of Bach1 as a heme-regulated and hypoxia-inducible repressor for transcription of the HO-1 gene has provided a missing link in the feedback control of heme catabolism. On the other hand, the human HO-1 gene promoter contains the (GT)n repeat polymorphism and a single nucleotide polymorphism (-427A --> T), both of which may contribute to fine-tuning of the transcription. Importantly, long (GT)n alleles are associated with susceptibility to smoking-induced emphysema or coronary artery disease, but may provide with resistance to cerebral malaria. The latter finding suggests a novel therapeutic strategy with inhibitors of HO-1 for the treatment of cerebral malaria. We discuss the potential regulatory role of Bach1 and HO-2 in heme catabolism and update the understanding of the regulation of HO-1 expression.