The heme oxygenase system and its functions in the brain.

The heme oxygenase (HO) system was identified in the early 1970s as a distinct microsomal enzyme system that catalyzes formation of bile pigments (Maines and Kappas, 1974). Up to the early 1990s the system was considered only as a "molecular wrecking ball" (Lane, 1998) for degradation of the heme molecule and production of toxic waste products, CO and bile pigments. For those years, the HO system remained relatively unknown to the research community. In a rather short span of the past 10 years following the discovery of high levels of a second form of the enzyme, HO-2, in the brain, suggesting that "heme oxygenase in the brain has functions aside from heme degradation" (Sun et al., 1990); concomitant with finding that another toxic gas, NO, is a signal molecule for generation of cGMP (Ignarro et al., 1982), the system was propelled into main stream research. This propulsion was fueled by the realization of the multiple and diverse functions of heme degradation products. Heme oxygenase has now found relevance in all kinds of human pathophysiology ranging from stroke, cancer, multiple sclerosis, and malaria to transplantation and immune response. As it turns out, its potential benefits are mesmerizing investigators in diverse fields (Lane, 1998). The most recent findings with HO-2 being a hemoprotein and potentially an intracellular "sink" for NO (McCoubrey et al., 1997a; Ding et al., 1999), together with the discovery of the third form of the enzyme, HO-3 (McCoubrey et al., 1997b), are likely to insure the widespread interest in the enzyme system in the coming years. The present review is intended to highlight molecular properties of HO isozymes and their likely functions in the brain. Extended reviews of the system are found in Maines (1992, 1997).