Icterus neonatorum, or neonatal jaundice, has long been recognized.¹ The term “kernicterus” was introduced in the early 1900s to refer to the yellow staining of the basal ganglia observed in infants who died with severe jaundice.² From the 1950s through the 1970s, because of a high incidence of Rh hemolytic disease and kernicterus, pediatricians were aggressive in treating jaundice.³ However, several factors have changed the management of jaundice. Studies in the 1980s and 1990s suggested that kernicterus from jaundice was rare and that too many infants were being treated unnecessarily.⁴⁷ Also, newborn infants were being discharged from the hospital . . .

Heme oxygenase-1 (HO-1), the rate-limiting enzyme in heme degradation, is an integral membrane protein of the smooth endoplasmic reticulum. However, we detected an HO-1 immunoreactive signal in the nucleus of cultured cells after exposure to hypoxia and heme or heme/hemopexin. Under these conditions, a faster migrating HO-1 immunoreactive band was enriched in nuclear extracts, suggesting that HO-1 was cleaved to allow nuclear entry. This was confirmed by the absence of immunoreactive signal with an antibody against the C terminus and the lack of a C-terminal sequence by gas chromatographymass spectrometry. Incubation with leptomycin B prior to hypoxia abolished nuclear HO-1 and the faster migrating band on Western analysis, suggesting that this process was facilitated by CRM1. Furthermore, preincubation with a cysteine protease inhibitor prevented nuclear entry of green fluorescent protein-labeled HO-1, demonstrating that protease-mediated C-terminal cleavage was also necessary for nuclear transport of HO-1. Nuclear localization was also associated with reduction of HO activity. HO-1 protein, whether it was enzymatically active or not, mediated activation of oxidant-responsive transcription factors, including activator protein-1. Nevertheless, nuclear HO-1 protected cells against hydrogen peroxide-mediated injury equally as well as cytoplasmic HO-1. We speculate that nuclear localization of HO-1 protein may serve to up-regulate genes that promote cytoprotection against oxidative stress.