Ontogeny of the Phase II cytosolic sulfotransferases and adverse drug reactions

描述（由申请人提供）：目前有多种儿科药物用于治疗患有不同疾病/病症的婴儿/儿童。这些药物在达到治疗目的的同时，也可能产生副作用。因此，两个重要的问题是：i）发育中的婴儿/儿童是否具有针对儿科药物不良反应的保护机制，以及ii）在婴儿/儿童发育期间，这种保护机制的出现如何有助于减轻这些不良反应。在人类和其他脊椎动物中，已知由SULT介导的硫酸化在异生物质的解毒中起主要作用。在这项拟议的研究中，特别感兴趣的是硫酸化可能在影响发育中的婴儿/儿童对儿科药物不良反应的易感性方面发挥的作用。在我们最近以斑马鱼为模型的研究中，我们证明了不同的SULT在胚胎发生到幼虫发育的不同阶段表现出不同的表达模式。此外，像人类SULT一样，斑马鱼SULT对许多测试药物显示出不同的硫酸化活性。鉴于至关重要的 这些酶在异生物质解毒中的作用，我们假设发育中的婴儿/儿童以及同样的斑马鱼胚胎/幼体对药物的任何潜在不良反应的易感性可能取决于相关药物硫酸化SULT的个体发育和组织/器官特异性表达。为了验证这一假设，将对通常用于治疗婴儿/儿童咳嗽/感冒和过敏/哮喘症状的选定儿科药物进行检测。这些药物，特别是在使用不当时，可能会引起不良反应，在极端情况下甚至会导致死亡。拟议的研究将解决与上述假设相关的三个问题，即SULT的药物硫酸化能力、其个体发育和组织/器官分布，以及相关药物硫酸化SULT在保护免受药物不良反应方面的参与。具体目标是：1.分析我们建立的人类和斑马鱼SULT对选定儿科药物的硫酸化活性，并阐明相关人类和斑马鱼药物硫酸化SULT的个体发育和组织/器官特异性表达;和2.验证相关药物硫酸化SULT在斑马鱼发育过程中对选定儿科药物不良反应的保护作用。 该项目的成功完成将揭示相关药物硫酸化SULT的个体发育和组织/器官特异性表达如何影响开发期间受试儿科药物对任何潜在不良反应的敏感性。随着对人类药物硫酸化SULT的个体发育及其底物特异性和催化效率的更好理解，所获得的信息最终可能有助于为不同年龄组的婴儿/儿童选择特定类型和剂量的儿科药物，从而减轻在发育过程中不同阶段可能发生的潜在不良反应。

DESCRIPTION (provided by applicant): A variety of pediatric drugs are currently in use for treating infants/children afflicted with different diseases/disorders. These drugs, while serving their therapeutic purposes, may exert adverse effects. Two important questions therefore are: i) whether the developing infants/children are equipped with mechanism(s) for protection against the adverse effects of pediatric drugs, and ii) how the emergence of such protection mechanism(s), during the infant/child development, may help alleviate these adverse effects. In humans and other vertebrates, sulfation as mediated by the SULTs is known to play a major role in the detoxification of xenobiotics. Of particular interest in this proposed research is the role that sulfation may play in influencing the susceptibility of the developing infants/children t the adverse effects of pediatric drugs. In our recent studies using the zebrafish as a model, we demonstrated that different SULTs exhibited distinct patterns of expression at different stages during embryogenesis on to larval development. Moreover, like human SULTs, zebrafish SULTs displayed differential sulfating activities toward a number of drugs tested. In view of the crucial role of these enzymes in the detoxification of xenobiotics, we hypothesize that the susceptibility of the developing infants/children, and likewise zebrafish embryos/larvae, to any potential adverse effects of drugs may be dependent on the ontogeny and tissue/organ-specific expression of relevant drug-sulfating SULTs. To verify this hypothesis, selected pediatric drugs that are commonly used for treating cough/cold and allergy/asthma symptoms in infants/children will be tested. These drugs, especially when improperly administered, may cause adverse effects including death in extreme cases. The proposed research will address three issues that are pertinent to the above-mentioned hypothesis, namely the drug- sulfating capacity of the SULTs, their ontogeny and tissue/organ distribution, and the involvement of relevant drug-sulfating SULTs in protection against the adverse effects of drugs. The specific aims are: 1. To analyze the sulfating activity of our established repertoires of human and zebrafish SULTs toward selected pediatric drugs, and to clarify the ontogeny and tissue/organ-specific expression of relevant human and zebrafish drug-sulfating SULTs; and 2. To verify the involvement of relevant drug-sulfating SULTs in protection against the adverse effects of selected pediatric drugs during zebrafish development. Successful completion of this project will reveal how the ontogeny and tissue/organ-specific expression of relevant drug-sulfating SULTs may influence the susceptibility to any potential adverse effects of the tested pediatric drugs during development. With better understanding about the ontogeny of human drug-sulfating SULTs and their substrate specificity and catalytic efficiency, the information obtained may eventually become useful in helping to choose particular types and doses of the pediatric drugs for different age groups of infants/ children, thereby alleviating potential adverse effects that may occur at different stages during development.