Function and induction of the microsomal heme oxygenase

Summary

The microsomal heme oxygenase system consists of heme oxygenase and NADPH-cytochrome P-450 reductase, and is considered to play a key role in the physiological heme catabolism to yield biliverdin in animals. Heme oxygenase purified from either pig spleen or rat liver has a minimum molecular weight of 32 000, and binds heme to form a 1:1 complex which exhibits properties resembled to those of hemoglobin and myoglobin. Heme degradation in the heme oxygenase reaction proceeds essentially as a series of autocatalytic oxidation of heme which is bound to heme oxygenase. The possible mechanism of heme degradation in the heme oxygenase reaction was presented.

Heme oxygenase can be induced by heme in various tissues such as liver, kidney and macrophages, possibly in a substrate-mediated induction. Heme oxygenase, especially in the liver, has also been shown to be inducible to various extents by a number of non-heme substances including insulin, epinephrine, endotoxin, carbon disulfide, certain metal ions, diethylmaleate, bromobenzene, chlorinated benzenes, and interferon- inducing agents, and some of those non-heme substances appear to induce heme oxygenase independently of the mediation by heme. Some principal features of heme oxygenase induction by hemin and several non-heme inducers were examined comparatively mainly in pig alveolar macrophages and in rat liver, especially taking the degree of heme saturation of tryptophan pyrrolase as a probe for estimating the intracellular heme concentration in the liver. Inductions by carbon disulfide, endotoxin, insulin, and epinephrine are likely to be mediated by heme, whereas inductions by metal ions, diethylmaleate, and bromobenzene appear to be caused by some unknown mechanism unrelated to heme. The induction by apparently heme-independent inducers has some organ specificity and perhaps species specificity. In the rat, however, the heme oxygenase induced by either hemin or non-heme substances and in either liver or kidney were immunochemically identical.

Cell-free synthesis of heme oxygenase directed by polysomes isolated from either pig alveolar macrophages or livers of rats treated with various inducers were examined by a combined use of [¹⁴C] or [³H]-labeled leucine and antibodies (IgG) specific to pig spleen heme oxygenase and rat liver heme oxygenase, respectively. In both macrophage and rat liver, free polysomes were the major site of heme oxygenase synthesis and the ability of polysomes to direct synthesis of heme oxygenase was greatly increased in the induced systems. Moreover, the abilities of polysomes isolated from livers of rats treated with hemin, Cd²⁺, and bromobenzene were proportional to the heme oxygenase activities in respective livers from which polysomes were prepared, indicating that all these inducers enhanced the synthesis of mRN A for heme oxygenase, giving rise to increased synthesis of heme oxygenase in the liver.