Therapeutic Use of Heme Analogs: Absorption in Intestine

Stanford University, Stanford CA

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Abstract

DESCRIPTION: (Scanned from the applicant's description): Neonatal jaundice occurs in 60-70 percent of newborn infants. It is due to hyperbilrubinemia caused not only by an overproduction of bilirubin (BR), but also by a transient failure to excrete this metabolite. Hyperbilirubinemia is exacerbated by hemolytic diseases, such as Rhesus isoimmunization and ABO incompatibility, which result in increased BR production, as well as diseases that result in decreased BR excretion. The rate-limiting enzyme in the production of BR is heme oxygenase (HO), and as such is a key therapeutic target. Inhibition of HO activity has been demonstrated to protect newborns from excessive hyperbilirubinemia. Heme analogs, metalloporphyrins (Mps), are potent competitive inhibitors of HO enzyme activity. The use of Mps as oral therapeutic agents may be an effective approach for the prevention and treatment of hyperbilirubinemia. However, one of the more poorly understood side effects of these compounds is that they also induce the production of new HO, which may negate their potential therapeutic utility. Therefore, a thorough understanding of the bioavailability, efficacy, and side effects of these drugs, both locally and systemically, is necessary for their use as effective therapeutics. In this project, we will use intravenous, direct intestinal administration, and oral delivery models in transgenic (Tg) mice where the transgene consists of the HO-i promoter and the luciferase reporter gene (luc). In this model, we will study the absorption of Mps by the intestine and their subsequent effects on local, target, and non-target organs. The systemic effects of Mps will initially be measured by two noninvasive assays: total body carbon monoxide (CO) excretion, an index of BR production, will be determined by gas chromatography; and, transcriptional regulation of HO-i will be monitored by in vivo imaging of reporter gene expression. Data from these in vivo assays will be used to correlate the ex vivo measurements of HO activity as well as HO mRNA and protein levels and will enable us to gain a overall understanding of the effects of Mps on HO biology. Further development and application of these combined in vivo measurements in this Tg model in conjunction with ex vivo assays is a powerful approach to assess the local and systemic effects of potential therapeutic compounds. Furthermore, these studies will provide answers regarding the chemotherapeutic potential of Mps for the treatment and prevention of neonatal hyperbilirubinemia.