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量产生，而且也是由于短暂的失败排泄这种代谢物。溶血性疾病，如恒河猴等免疫和ABO不相容，导致胆红素产生增加，以及导致胆红素排泄减少的疾病，加重了高胆红素血症。胆红素生成的限速酶是血红素加氧酶（HO），因此是一个关键的治疗靶点。抑制HO活性已被证明可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。在这个竞争性的更新中，我们建议从逻辑上扩展我们的发现，从之前的资助提案中研究口服中卟啉锡（SnMP），其他选择的血红素类似物和HO的非卟啉抑制剂对血红素负载的新生小鼠的功效，这是一个类似于人类婴儿的模型，其胆红素产生增加。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，在另一种血红素负荷后的反应，以及这种反应的介导机制。在之前的资助期内，我们继续开发和验证检测，以监测体内胆红素生成和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上的调控和表达。这些方法在新生小鼠模型中的应用是我们以前在成年啮齿动物模型中工作的自然延伸。这个项目的结果将通过提供与酶靶的直接作用、其表达以及随后对新生动物的短期和长期影响有关的空间和时间信息，帮助设计这些和相关化合物的临床研究。该应用的具体目的仍然是评估口服选定的Mps（一类血红素类似物）的有效性和安全性，因为它们通过抑制HO活性对新生儿黄疸具有治疗价值。我们将进一步扩大这些研究，对选定的Mps进行全面评估，我们已经证明Mps是口服吸收的，以及HO的非卟啉抑制剂，但特别强调研究它们对大脑和其他非靶组织的可及性，以及它们在血红素负荷新生小鼠中的短期和长期影响。

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.