Effect of light exposure on metalloporphyrin-treated newborn mice

Abstract

Background: Neonatal hyperbilirubinemia arises from increased bilirubin production and decreased bilirubin elimination. Although phototherapy safely and effectively reduces bilirubin levels, recent evidence shows that it has adverse effects. Therefore, alternative treatments are warranted. Metalloporphyrins, competitive inhibitors of heme oxygenase (hO), the rate-limiting enzyme in bilirubin production, effectively reduce bilirubin formation; however, many are photoreactive. here, we investigated possible photosensitizing effects of chromium mesoporphyrin (crMP) and zinc deuteroporphyrin bis-glycol (ZnBG). Methods and results: Administration of crMP or ZnBG to 3-d-old mouse pups (3.75-30.0 µmol/kg intraperitoneally) and exposure to cool white (F20T12cW) and blue (TL20W/52) fluorescent lights (+L) for 3 h, resulted in a dose-dependent mortality (50% lethal dose (LD50) = 21.5 and 19.5 µmol/kg, respectively). In contrast to ZnBG, there was no significant difference in survival between the crMP+L and crMP groups. Following 30 µmol/kg ZnBG+L, we found significant weight loss, decreased liver antioxidant capacities, and increased aspartate aminotransaminase levels. At 6-d post-light exposure, ZnBG+L-treated pups showed gross and histologic skin changes at doses >7.5 µmol/kg. No lethality was observed following treatment with 30 µmol ZnBG/kg plus exposure to blue light-emitting diodes. Phototoxicity of ZnBG was dependent on light source, emission spectrum, and irradiance. conclusion: Low doses of ZnBG (<3.75 µmol/kg) retained maximal hO inhibitory potency without photosensitizing effects, and therefore are potentially useful in treating neonatal hyperbilirubinemia.

Heme-Mediated SPI-C Induction Promotes Monocyte Differentiation into Iron-Recycling Macrophages

“…Bilirubin and biliverdin failed to induce SPIC-EGFP in Spic igfp/igfp BMDM (Figure 2D). Furthermore, iron chelation by deferoxamine or HO1 inhibition by chromium mesoporphyrin (Crmp) (Schulz et al, 2012b) failed to inhibit heme-mediated SPIC-EGFP induction (Figures S4B and S4C). These results argue against a role of heme metabolites in Spic induction.…”

Inhibition of heme oxygenase activity using a microparticle formulation of zinc protoporphyrin in an acute hemolytic newborn mouse model

“…In addition, treated infants showed a photosensitivity when phototherapy was applied (10). In addition, we have found that zinc deuteroporphyrin bis-glycol (ZnBG) and chromium mesoporphyrin (CrMP) have photo-and chemical toxicity, respectively, despite both being highly potent (26). And, except in two healthy adult studies showing no oral absorbance of SnPP (27) and SnMP (28), all the Mps tested in earlier trials have been administered parenterally (i.v.…”

Effects of light on metalloporphyrin-treated newborn mice

“…In a recent publication (31), we demonstrated the possible photosensitising effects of two promising Mps for use in the prevention of neonatal jaundice, CrMP and ZnBG. We chose these two compounds because both are orally absorbed, relatively potent with minimal photoreactivity in the desirable dose range and minimally upregulates HO-1 transcription.…”

“…HO activity was calculated as pmol CO/h/mg fresh weight (FW) and then expressed as mean ± SD% of control values. To evaluate toxicity, pups were treated similarly and then immediately placed for 3 h under fluorescent tubes (2 cool white/1 blue TL52) to test for phototoxicity or kept in the dark to test for chemical toxicity . Overall survival of pups was then monitored up to 1 week.…”

“…Such a drug should have a low I 50 [i.e. high inhibitory potency, such as that found with SnMP, chromium mesoporphyrin (CrMP) and zinc bis glycol porphyrin (ZnBG)]; should not be a photosensitiser (unlike SnMP) ; should be orally absorbable (like CrMP and ZnBG); should not cross the blood–brain barrier; should be short‐acting ; should not substantially upregulate HO‐1 mRNA, protein, or activity; and should not be degraded with the subsequent release of the sequestered metal ion . We have also observed that the potential therapeutic effect of inhibiting HO activity may be offset by increases in HO‐1 transcription, which may arise following the use of some Mps in animal models .…”