Metalloporphyrins (MTP) are currently considered for therapy of neonatal jaundice. They are competitive inhibitors of heme oxygenase (HO), the rate limiting enzyme in bilirubin production. However, previous studies in our laboratory have shown that HO-1 is induced by certain MTP. Because oxidative stress is a known stimulus for regulation of HO-1 mRNA, we hypothesized that MTP may thus induce HO-1 mRNA by resulting in oxidative stress. Therefore, cultured hamster fibroblasts were incubated for 4, 24, or 48 hours with 10μM zinc mesoporphyrin (ZnMP), zinc protoporphyrin (ZnPP), tin mesoporphyrin (SnMP), tin protoporphyrin (SnPP), chromium mesoporphyrin(CrMP), or chromium protoporphyrin (CrPP), MTP chosen for their potential clinical applications. Cells were analyzed for total HO activity by gas chromatography, HO-1 protein by Western blot analysis, and HO-1 mRNA by Northern blot analysis. We also determined LDH release, a measurement of general cell injury, and total glutathione levels and thiobarbituric acid reactive substance (TBA-RS) as indices of oxidative stress.Table

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Although previous studies demonstrated that ZnMP and ZnPP strongly induced HO-1 mRNA and that CrMP also significantly induced HO-1 mRNA, but to a lesser extent, at 48 hours,(1) in this study ZnMP was the only MTP associated with increased lipid peroxidation. Furthermore, glutathione levels were not affected by any MTP. We therefore cannot conclude that induction of HO-1 mRNA by MTP is solely regulated by oxidative stress. We speculate that metal related induction of HO-1 may occur with some MTP.