Therapeutic Use of Heme Analogs: Absorption in Intestine

Stanford University, Stanford CA

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Abstract

DESCRIPTION (provided by applicant): Neonatal jaundice occurs in 60-70% of all newborn infants. It is due to hyperbilirubinemia caused not only by an overproduction of bilirubin, 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 bilirubin production, as well as diseases that result in decreased bilirubin excretion. The rate- limiting enzyme in the production of bilirubin is heme oxygenase (HO), and as such is a key therapeutic target. Inhibition of HO activity has been shown 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. In this competing renewal, we propose to logically extend our findings from the previous funded proposal to investigate the efficacy of the oral administration of tin mesoporphyrin (SnMP), other selected heme analogs, and non-porphyrin inhibitors of HO to the heme-loaded newborn mouse, a model analogous to the human infant with increased bilirubin production. In this evaluation, we will assess their accessibility to the brain, their short- and long-term effects, response following another heme load, and the mechanisms by which this response is mediated. In the previous funding period, we have continued to develop and validate assays to monitor both in vivo bilirubin production and HO-1 transcriptional patterns and in vitro enzymatic activity of HO so that we can evaluate regulation and expression at these levels. Application of these approaches to the newborn mouse model is a natural extension of our previous work with the adult rodent models. The results of this project will assist in the design of clinical studies for these and related compounds by providing both spatial and temporal information pertaining to direct effects on the enzymatic target, its expression, and subsequent short- and long-term effects on the newborn animal. The specific aims of this application are still directed at evaluating the efficacy and safety of the oral administration of selected Mps, a class of heme analogs, for their therapeutic value to neonatal jaundice through inhibition of HO activity. We will further expand these studies to an overall evaluation of selected Mps, which we have shown to be orally absorbed, and non-porphyrin inhibitors of HO, but with particular emphasis on the study of their accessibility to the brain and other non-target tissues as well as their short- and long-term effects in the heme-loaded newborn mouse.