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.
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Authors | Cynthia X He, Claire M Campbell, Hui Zhao, Flora S Kalish, Stephanie Schulz, Hendrik J Vreman, Ronald J Wong, David K Stevenson |
Journal | Pediatric research
(Pediatr Res)
Vol. 70
Issue 5
Pg. 467-72
(Nov 2011)
ISSN: 1530-0447 [Electronic] United States |
PMID | 21785387
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Deuteroporphyrins
- zinc deuteroporphyrin IX 2,4-bis(glycol)
- Carbon Monoxide
- Heme Oxygenase (Decyclizing)
- Bilirubin
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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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