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Effects of zinc deuteroporphyrin bis glycol on newborn mice after heme loading.

Abstract
Infants with hemolytic diseases frequently develop hyperbilirubinemia and are treated with phototherapy, which only eliminates bilirubin after its production. A better strategy might be to directly inhibit heme oxygenase (HO), the rate-limiting enzyme in bilirubin production. Metalloporphyrins (Mps) are heme analogs that competitively inhibit HO activity in vitro and in vivo and suppress plasma bilirubin levels in vivo. A promising Mp, zinc deuteroporphyrin bis glycol (ZnBG), is orally absorbed and effectively inhibits HO activity at relatively low doses. We determined the I(50) (the dose needed to inhibit HO activity by 50%) of orally administered ZnBG in vivo and then evaluated ZnBG's effects on in vivo bilirubin production, HO activity, HO protein levels, and HO-1 gene expression in newborn mice after heme loading, a model analogous to a hemolytic infant. The I(50) of ZnBG was found to be 4.0 μmol/kg body weight (BW). At a dose of 15 μmol/kg BW, ZnBG reduced in vivo bilirubin production, inhibited heme-induced liver HO activity and spleen HO activity to and below baseline, respectively, transiently induced liver and spleen HO-1 gene transcription, and induced liver and spleen HO-1 protein levels. We conclude that ZnBG may be an attractive compound for treating severe neonatal hyperbilirubinemia caused by hemolytic disease.
AuthorsCynthia X He, Claire M Campbell, Hui Zhao, Flora S Kalish, Stephanie Schulz, Hendrik J Vreman, Ronald J Wong, David K Stevenson
JournalPediatric research (Pediatr Res) Vol. 70 Issue 5 Pg. 467-72 (Nov 2011) ISSN: 1530-0447 [Electronic] United States
PMID21785387 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Deuteroporphyrins
  • zinc deuteroporphyrin IX 2,4-bis(glycol)
  • Carbon Monoxide
  • Heme Oxygenase (Decyclizing)
  • Bilirubin
Topics
  • Animals
  • Animals, Newborn
  • Bilirubin (blood)
  • Blotting, Western
  • Carbon Monoxide (analysis)
  • Chromatography, Gas
  • Deuteroporphyrins (pharmacology)
  • Dose-Response Relationship, Drug
  • Gene Expression Regulation (drug effects)
  • Heme Oxygenase (Decyclizing) (antagonists & inhibitors, genetics, metabolism)
  • Hyperbilirubinemia, Neonatal (prevention & control)
  • Liver (drug effects, metabolism)
  • Mice
  • Real-Time Polymerase Chain Reaction
  • Spleen (drug effects, metabolism)

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