Heme oxygenase (HO) is the heme-degrading enzyme which generates biliverdin, ferrous iron and carbon monoxide (CO). Recent investigation has revealed that the physiologic significance of the HO reaction results not only from its ability to execute heme detoxification and iron recycling, but also from the biological actions of its reaction products such as CO, a gaseous messenger molecule, or biliverdin/bilirubin, bile pigments possessing oxyradical-scavenging properties. Because of its capability to degrade free heme as a prosthetic molecule required for the enzyme activity of heme enzymes, up-regulation of stress-inducible HO-1 could alter the homeostasis of organ functions and thus account for certain pathophysiological features of organ dysfunction in a variety of disease conditions. Such modification occurs not only through biological actions of CO and bilirubin, but also through down-regulation of heme enzymes such as nitric oxide (NO) synthase and other cytochrome P450 monooxygenases. Like NO, CO has been thought to utilize soluble guanylate cyclase, a cyclic GMP-producing heme enzyme, to execute signal transduction, but its ability to activate the enzyme in vitro turned out to be far less than that of NO. These circumstances lead investigators to search for novel signaling mechanisms that operate through cyclic GMP-independent mechanisms. This review article provides an overview of the pathophysiological significance of the HO/CO system and summarizes the controversies regarding CO-mediated signaling mechanisms.
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