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

Abstract

BACKGROUND:

Increased bilirubin production due to hemolysis can lead to neonatal hyperbilirubinemia. Inhibition of heme oxygenase (HO), the rate-limiting enzyme in heme catabolism, by metalloporphyrins (Mps) may be an ideal preventive strategy for neonatal hemolytic disease. Zinc protoporphyrin (ZnPP) is a naturally occurring Mp, potent, not phototoxic, with minimal HO-1 upregulation, but is not orally absorbed. Recently, we designed a lipid-based ZnPP formulation (ZnPP-Lipid), which is orally absorbed by newborn mice. Here, we evaluated the efficacy of ZnPP-Lipid in heme-loaded newborn mice, a model analogous to hemolytic infants.

METHODS:

After 24 h of heme administration (30 µmol/kg s.c.), 4-d-old mice were given 30 µmol ZnPP-Lipid/kg via intragastric injections. After 3 h, liver and brain HO activity were measured. HO-1 upregulation was assessed by determinations of HO-1 protein, promoter activity, and mRNA by Western blot, in vivo bioluminescence imaging, and RT-PCR, respectively.

RESULTS:

After heme loading, liver HO activity significantly increased ~1.6-fold, which was inhibited in a dose-dependent manner by ZnPP-Lipid. A dose of 30 µmol/kg returned activity to control levels. Brain HO activity was not inhibited. No significant increases in liver and brain HO-1 protein, promoter activity, and mRNA were observed.

CONCLUSION:

ZnPP-Lipid is effective and thus has potential for treating neonatal hyperbilirubinemia due to hemolysis.

• Authors: Kazumichi Fujioka, Flora Kalish, Ronald J Wong, David K Stevenson
• Journal: Pediatric research (Pediatr Res) Vol. 79 Issue 2 Pg. 251-7 (Feb 2016) ISSN: 1530-0447 [Electronic] United States
• PMID: 26488552 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Lipids
• Membrane Proteins
• Protoporphyrins
• zinc protoporphyrin
• Heme Oxygenase-1
• Hmox1 protein, mouse

Topics

• Administration, Oral
• Animals
• Animals, Newborn
• Brain (drug effects, enzymology)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Drug Compounding
• Enzyme Inhibitors (administration & dosage, chemistry, pharmacology)
• Heme Oxygenase-1 (antagonists & inhibitors, genetics, metabolism)
• Hemolysis (drug effects)
• Hyperbilirubinemia, Neonatal (blood, enzymology, genetics, prevention & control)
• Lipids (chemistry)
• Liver (drug effects, enzymology)
• Membrane Proteins (antagonists & inhibitors, genetics, metabolism)
• Mice
• Particle Size
• Protoporphyrins (administration & dosage, chemistry, pharmacology)
• Time Factors