Systemic Effects of Orally-Administered Zinc and Tin (IV) Metalloporphyrins on Heme Oxygenase Expression in Mice

Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305-5208, USA.
Pediatric Research (Impact Factor: 2.31). 06/2006; 59(5):667-72. DOI: 10.1203/01.pdr.0000215088.71481.a6
Source: PubMed


Some metalloporphyrins (Mps) inhibit heme oxygenase (HO), the rate-limiting enzyme in the production of bilirubin, and are potential compounds for the treatment of neonatal jaundice. We studied the safety and efficacy of Mps following oral administration. Adult HO-1-luc reporter mice were administered 30 micromol/kg body weight of tin mesoporphyrin (SnMP), zinc bis glycol deuteroporphyrin (ZnBG), or zinc protoporphyrin (ZnPP), or vehicle by oral gavage. Bilirubin production was measured as total body carbon monoxide (CO) excretion (VeCO). HO activity was quantitated via CO measurements by gas chromatography. HO-1 protein was determined by Western blot. HO-1 transcription levels were assessed by in vivo bioluminescence imaging. A significant 28% decrease in bilirubin production occurred within 3 h of SnMP treatment and persisted beyond 48 h. Bilirubin production decreased 15% and 9% by 3 h after administration of ZnBG and ZnPP, respectively, but returned to baseline within 48 h. Maximal inhibition of liver, spleen, and intestine HO activity was seen at 3 h with inhibitory effects decreasing in the order: SnMP > or = ZnBG > or = ZnPP. After SnMP treatment, HO-1 transcription increased 5.7-fold after 24 h. Furthermore, liver and spleen HO-1 protein significantly increased 3.7- and 2.0-fold, respectively, after 24 h. HO-1 transcription and protein were not affected in ZnBG- or ZnPP-treated mice. We conclude that the three Mps are absorbed at different rates in the mouse and affect bilirubin production and HO-1 expression in a tissue- and time-dependent manner.

Download full-text


Available from: Christopher H Contag, May 20, 2014
13 Reads
  • Source
    • "Moreover, SnMP showed a very low excretion rate in feces and urine, suggesting a rapid uptake into intra- or extravascular spaces and tissue binding (Galbraith and Kappas, 1989). Effective doses in human adults and neonates ranged from 1 to 6 μmol/kg BW (Valaes et al., 1994, 1998; Kappas et al., 1995; Martinez et al., 1999) and in animal studies from 1 to 30 μmol/kg BW (Drummond et al., 1987; Morioka et al., 2006). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Metalloporphyrins are structural analogs of heme and their potential use in the management of neonatal hyperbilirubinemia has been the subject of considerable research for more than three decades. The pharmacological basis for using this class of compounds to control bilirubin levels is the targeted blockade of bilirubin production through the competitive inhibition of heme oxygenase (HO), the rate-limiting enzyme in the bilirubin production pathway. Ongoing research continues in the pursuit of identifying ideal metalloporphyrins, which are safe and effective, by defining therapeutic windows and targeted interventions for the treatment of excessive neonatal hyperbilirubinemia.
    Frontiers in Pharmacology 04/2012; 3:68. DOI:10.3389/fphar.2012.00068 · 3.80 Impact Factor
  • Source
    • "One transcriptional consequence of Fh1 deficiency is Hmox1 upregulation. Since Hmox1 is cardioprotective (Melo et al., 2002; Piantadosi et al., 2008; Soares et al., 1998; Yet et al., 2001), we hypothesized that Hmox1 contributed to fumaraterelated cardioprotection and assessed the effect of zinc deuteroporphyrin 2,4-bis glycol (ZnBG), a well-established and relatively specific Hmox1 inhibitor (Vreman et al., 1991; Appleton et al., 1999; Zhang et al., 2002; Morioka et al., 2006; Czibik et al., 2009). Inhibition of Hmox1 by ZnBG abrogated cardioprotection in the Fh1 KO hearts (33.3% ± 2.2% control; 11.4% ± 1.5% Fh1 KO; 30.1% ± 2.7% control + ZnBG; 35.2% ± 4.6% Fh1 KO + ZnBG; Fh1 KO ANOVA p < 0.001 versus all other groups) (Figure 4E). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The citric acid cycle (CAC) metabolite fumarate has been proposed to be cardioprotective; however, its mechanisms of action remain to be determined. To augment cardiac fumarate levels and to assess fumarate's cardioprotective properties, we generated fumarate hydratase (Fh1) cardiac knockout (KO) mice. These fumarate-replete hearts were robustly protected from ischemia-reperfusion injury (I/R). To compensate for the loss of Fh1 activity, KO hearts maintain ATP levels in part by channeling amino acids into the CAC. In addition, by stabilizing the transcriptional regulator Nrf2, Fh1 KO hearts upregulate protective antioxidant response element genes. Supporting the importance of the latter mechanism, clinically relevant doses of dimethylfumarate upregulated Nrf2 and its target genes, hence protecting control hearts, but failed to similarly protect Nrf2-KO hearts in an in vivo model of myocardial infarction. We propose that clinically established fumarate derivatives activate the Nrf2 pathway and are readily testable cytoprotective agents.
    Cell metabolism 03/2012; 15(3):361-71. DOI:10.1016/j.cmet.2012.01.017 · 17.57 Impact Factor
  • Source
    • "For this purpose often transgenic animals are generated expressing luciferase either ubiquitously or under the control of a regulated promoter. As bioluminescence will occur only when the controlling promoter is active, this technique enables the monitoring of spatiotemporal changes of protein expression in vivo e.g., as applied for analysis of the heme oxygenase-1 that plays a key role in development and where disregulation is often associated with jaundice in neonates [84, 85]. Transgenic mice expressing luciferase under the control of a lobe-specific promoter were used to investigate the early onset of retinoblastoma [86] or to generate luciferase expressing haematopoietic stem cells used for the visualization of leukemogenesis after transplantation in bone-marrow-depleted mice [87]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: To obtain information on the occurrence and location of molecular events as well as to track target-specific probes such as antibodies or peptides, drugs or even cells non-invasively over time, optical imaging (OI) technologies are increasingly applied. Although OI strongly contributes to the advances made in preclinical research, it is so far, with the exception of optical coherence tomography (OCT), only very sparingly applied in clinical settings. Nevertheless, as OI technologies evolve and improve continuously and represent relatively inexpensive and harmful methods, their implementation as clinical tools for the assessment of children disease is increasing. This review focuses on the current preclinical and clinical applications as well as on the future potential of OI in the clinical routine. Herein, we summarize the development of different fluorescence and bioluminescence imaging techniques for microscopic and macroscopic visualization of microstructures and biological processes. In addition, we discuss advantages and limitations of optical probes with distinct mechanisms of target-detection as well as of different bioluminescent reporter systems. Particular attention has been given to the use of near-infrared (NIR) fluorescent probes enabling observation of molecular events in deeper tissue.
    Pediatric Radiology 02/2011; 41(2):161-75. DOI:10.1007/s00247-010-1907-0 · 1.57 Impact Factor
Show more