Cytoprotective role of heme oxygenase-1 and heme degradation derived end products in liver injury

Abstract

The activation of heme oxygenase-1 (HO-1) appears to be an endogenous defensive mechanism used by cells to reduce inflammation and tissue damage in a number of injury models. HO-1, a stress-responsive enzyme that catabolizes heme into carbon monoxide (CO), biliverdin and iron, has previously been shown to protect grafts from ischemia/reperfusion and rejection. In addition, the products of the HO-catalyzed reaction, particularly CO and biliverdin/bilirubin, have been shown to exert protective effects in the liver against a number of stimuli, as in chronic hepatitis C and in transplanted liver grafts. Furthermore, the induction of HO-1 expression can protect the liver against damage caused by a number of chemical compounds. More specifically, the CO derived from HO-1-mediated heme catabolism has been shown to be involved in the regulation of inflammation; furthermore, administration of low concentrations of exogenous CO has a protective effect against inflammation. Both murine and human HO-1 deficiencies have systemic manifestations associated with iron metabolism, such as hepatic overload (with signs of a chronic hepatitis) and iron deficiency anemia (with paradoxical increased levels of ferritin). Hypoxia induces HO-1 expression in multiple rodent, bovine and monkey cell lines, but interestingly, hypoxia represses expression of the human HO-1 gene in a variety of human cell types (endothelial cells, epithelial cells, T cells). These data suggest that HO-1 and CO are promising novel therapeutic molecules for patients with inflammatory diseases. In this review, we present what is currently known regarding the role of HO-1 in liver injuries and in particular, we focus on the implications of targeted induction of HO-1 as a potential therapeutic strategy to protect the liver against chemically induced injury.

Keywords: Bilirubin; Heme oxygenases; Hepatitis C; Hypoxia; Immunoregulatory; Kupffer cells; Liver ischemia; Polymorphisms.

Figure 1

The heme oxygenase enzyme reaction. Heme is enzymatically degraded to yield carbon monoxide, iron and biliverdin (which is converted into bilirubin in a coupled reaction). CO: Carbon monoxide; NADP: Nicotinamide adenine dinucleotide phosphate; NADPH: β-Nicotinamide adenine dinucleotide 2'-phosphate reduced tetrasodium salt.

Figure 2

A variety of stimuli induce heme oxygenase-1 expression, a wide array of hepatotoxic chemicals and conditions conferring an adaptive cytoprotective response. HO-1: Heme oxygenase-1; UV: Ultraviolet.