Ontogeny of the Phase II cytosolic sulfotransferases and adverse drug reactions

说明(申请人提供)：目前有多种儿科药物用于治疗患有不同疾病/障碍的婴儿/儿童。这些药物在达到治疗目的的同时，也可能产生不良影响。因此，两个重要的问题是：i)发育中的婴儿/儿童是否配备了针对儿科药物不良影响的保护机制(S)，以及ii)这种保护机制(S)在婴儿/儿童发育期间的出现如何有助于减轻这些不良影响。在人类和其他脊椎动物中，由硫磺介导的硫酸盐化被认为在外源生物的解毒中发挥了重要作用。在这项拟议的研究中，特别感兴趣的是硫酸盐化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可能发挥的作用。在我们最近以斑马鱼为模型的研究中，我们发现不同的斑马鱼在胚胎发生到幼体发育的不同阶段表现出不同的表达模式。此外，像人类硫磺一样，斑马鱼硫磺对一些被测试的药物表现出不同的硫酸盐化活性。鉴于关键的 关于这些酶在外源物质解毒中的作用，我们假设发育中的婴儿/儿童以及斑马鱼胚胎/幼体对任何潜在的药物不良影响的敏感性可能取决于相关药物硫化结果的个体发育和组织/器官特异性表达。为了验证这一假设，将测试一些通常用于治疗婴儿/儿童咳嗽/感冒和过敏/哮喘症状的儿科药物。这些药物，特别是在使用不当的情况下，可能会导致不良反应，包括极端情况下的死亡。拟议的研究将涉及与上述假设有关的三个问题，即硫酸盐的药物硫化能力、其个体发育和组织/器官分布，以及相关药物硫酸盐在保护药物免受不良影响方面的参与。具体目的是：1.分析我们建立的人类和斑马鱼硫酸盐对选定的儿科药物的硫化活性，并阐明相关的人和斑马鱼药物硫酸盐的个体发育和组织/器官特异性表达；以及2.验证相关的药物硫酸盐在斑马鱼发育过程中对选定的儿童药物的不良影响的保护作用。该项目的成功完成将揭示相关药物磺化结果的个体发育和组织/器官特异性表达如何影响所测试的儿科药物在开发过程中对任何潜在不良反应的敏感性。随着更好地了解人类药物硫酸盐的个体发育及其底物特异性和催化效率，所获得的信息最终可能有助于为不同年龄段的婴儿/儿童选择特定类型和剂量的儿科药物，从而减轻在发育不同阶段可能发生的潜在不良影响。 与公共卫生相关：拟议的研究旨在获得关于胞液硫转移酶(Sults)在保护儿科药物在发育过程中的不良影响中所起作用的分子机制的基本信息。所获得的信息还可能有助于将斑马鱼确立为一种有用的系统，用于全面审查药物的不良影响。

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. PUBLIC HEALTH RELEVANCE: The proposed studies are designed to obtain fundamental information concerning the molecular mechanisms underlying the role of the cytosolic sulfotransferases (SULTs) in protection against the adverse effects of pediatric drugs during the developmental process. The information obtained may also help establish the zebrafish as a useful system for scrutinizing the adverse effects of drugs in general.