Ontogeny of the Phase II cytosolic sulfotransferases and adverse drug reactions

II期胞质磺基转移酶的个体发育和药物不良反应

• 批准号: 8554775
• 负责人: MING-CHEH LIU
• 金额: $ 7.11万
• 依托单位: UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-30 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8554775
• 关键词: Acetaminophen; Address; Adverse drug effect; Adverse effects; Albuterol; Animal Model; Anti-Asthmatic Agents; Asthma; Cessation of life; Child; Child Development; Childhood; Coughing; Development; Developmental Process; Dextromethorphan; Diet; Disease; Dose; Drug Design; Drug Metabolic Detoxication; Embryo; Embryonic Development; Enzymes; Exhibits; Goals; Growth; Human; Hypersensitivity; Infant; Inorganic Sulfates; Larva; Mediating; Modeling; Molecular; Organ; Pattern; Pharmaceutical Preparations; Phase; Physiological; Play; Predisposition; Reaction; Research; Research Design; Role; Specimen; Staging; Substrate Specificity; Symptoms; System; Testing; Therapeutic; Tissues; Unspecified or Sulfate Ion Sulfates; Vertebrates; Xenobiotics; Zebrafish; age group; design; drug metabolism; drug testing; human tissue; interest; mRNA Differential Displays; sulfation; sulfotransferase; zebrafish development

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.

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/障碍的婴儿/儿童。这些药物在达到治疗目的的同时，可能会产生副作用。因此，两个重要的问题是：1)发育中的婴儿/儿童是否具备针对儿科药物不良反应的保护机制；2)在婴儿/儿童发育过程中，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，SULTs介导的硫酸化在外源药物的解毒中起着重要作用。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SULTs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，与人类SULTs一样，斑马鱼SULTs对许多测试药物表现出不同的硫酸化活性。鉴于至关重要

项目成果

Molecular cloning and characterization of common marmoset SULT1C subfamily members that catalyze the sulfation of thyroid hormones

催化甲状腺激素硫酸化的普通狨猴 SULT1C 亚家族成员的分子克隆和表征

• DOI: 10.1093/bbb/zbab141
• 发表时间: 2021
• 期刊: Bioscience, Biotechnology, and Biochemistry
• 作者: Kurogi Katsuhisa;Manabe Yoko;Liu Ming-Cheh;Suiko Masahito;Sakakibara Yoichi
• 通讯作者: Sakakibara Yoichi

Sulfation of opioid drugs by human cytosolic sulfotransferases: metabolic labeling study and enzymatic analysis.

• DOI: 10.1016/j.ejps.2014.05.003
• 发表时间: 2014-10-01
• 期刊: EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
• 影响因子: 4.6
• 作者: Kurogi, Katsuhisa;Chepak, Andriy;Hanrahan, Michael T.;Liu, Ming-Yih;Sakakibara, Yoichi;Suiko, Masahito;Liu, Ming-Cheh
• 通讯作者: Liu, Ming-Cheh

Sulfate conjugation of daphnetin by the human cytosolic sulfotransferases.

• DOI: 10.1016/j.jep.2016.05.041
• 发表时间: 2016-08-02
• 期刊: Journal of ethnopharmacology
• 影响因子: 5.4
• 作者: Han Z;Xi Y;Luo L;Zhou C;Kurogi K;Sakakibara Y;Suiko M;Liu MC
• 通讯作者: Liu MC