Heme Oxygenase-1

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Schmid and coworkers1 were the first to report on the presence of heme oxygenase (HO) in liver microsomes capable of degrading heme to bilirubin, and this activity was subsequently dissociated from cytochrome P-450.2,3 HO catalyzes the first and rate-limiting step in the oxidative degradation of heme (Fe-protoporphyrin-IX) to carbon monoxide (CO), ferrous iron (Fe2+), and biliverdin-IX (Figure 1). The enzyme binds heme in a 1:1 molar complex, and HO-bound heme acts as prosthetic group and substrate. The reaction requires 3 molecules of molecular oxygen (O2) per heme molecule oxidized and reducing equivalents derived from nicotinamide adenine dinucleotide phosphate or nicotinamide adenine dinucleotide (reduced form) and transferred to the oxygenase via nicotinamide adenine dinucleotide phosphate:cytochrome P-450 reductase. Regiospecific oxidation of heme is achieved in a stepwise reaction, with α-meso-hydroxyheme and verdoheme as intermediates, and the dissociation of CO followed by that of Fe2+.4 The release of biliverdin from HO is accelerated by biliverdin reductase, which reduces the green pigment to bilirubin-IX,4 which is then excreted into bile as the glucuronic acid conjugate. Figure 1. Oxidative metabolism of heme by HO and biliverdin reductase, giving rise to CO, iron, biliverdin, and bilirubin. Originally, the interest in HO was related to its well-established function in heme catabolism and the turnover of erythrocytes. For many years, CO and bilirubin were regarded as toxic waste byproducts of the HO reaction, but in 1987, a potential beneficial role of bilirubin was proposed5 based on the in vitro antioxidant activities of the pigment. Over the last decade, however, the interest in HO has shifted greatly from a metabolic to a protective function of the enzyme in a variety of conditions associated with cellular stress and pathologies, and this has been the subject of excellent recent reviews.6,7 The …