Therapeutic Use of Heme Analogs: Absorption in Intestine

描述（由申请人提供）：新生儿黄疸发生在所有新生儿的60-70%。这是由于高胆红素血症引起的，不仅是由于胆红素的过度产生，而且也是由于短暂的无法排出这种代谢产物。高胆红素血症会因溶血性疾病而加重，如导致胆红素产生增加的恒河猴同种免疫和ABO不相容性，以及导致胆红素排泄减少的疾病。胆红素产生中的限速酶是血红素加氧酶（HO），因此是关键的治疗靶标。HO活性的抑制已被证明可以保护新生儿免于过度高胆红素血症。血红素类似物，金属卟啉（Mps），是HO酶活性的有效竞争性抑制剂。使用Mps作为口服治疗剂可能是预防和治疗高胆红素血症的有效途径。在这种竞争性的更新，我们建议从逻辑上扩展我们的研究结果从以前的资助建议，以调查口服给药的疗效锡中卟啉（SnMP），其他选定的血红素类似物，和非卟啉抑制剂HO血红素负载的新生小鼠，一个模型类似于人类婴儿增加胆红素的生产。在这项评估中，我们将评估它们对大脑的可及性，它们的短期和长期影响，另一个血红素负荷后的反应，以及介导这种反应的机制。在之前的资助期间，我们继续开发和验证检测方法，以监测体内胆红素产生和HO-1转录模式以及HO的体外酶活性，以便我们可以评估这些水平的调控和表达。将这些方法应用于新生小鼠模型是我们先前使用成年啮齿动物模型的工作的自然延伸。该项目的结果将有助于这些和相关化合物的临床研究的设计，通过提供有关对酶靶点的直接影响，其表达以及随后对新生动物的短期和长期影响的空间和时间信息。本申请的具体目的仍然在于评价口服施用选定的Mps（一类血红素类似物）的功效和安全性，以评价其通过抑制HO活性对新生儿黄疸的治疗价值。我们将进一步扩大这些研究的总体评价选定的Mps，我们已经证明是口服吸收，和非卟啉抑制剂的HO，但特别强调的研究，他们的可及性的大脑和其他非靶组织，以及他们的短期和长期的影响，在血红素加载的新生小鼠。

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.