硫酸结合代谢途径介导药物不良反应的分子机制和预防策略研究

Sulfation is an important phase II drug metabolic reaction, which is usually detoxification pathway. In recent years, some literatures reported adverse drug reactions (ADR) were mediated by sulfation, such as hepatotoxicity and genotoxicity of tamoxifen, severe rash of nevirapine, and moderate hepatotoxicity of 3-n-butylphthalide (NBP). However, underlying molecular mechanism of toxicity were limited to the in vitro metabolic bioactivation. The investigation on the relationship between in vitro metabolic bioactivation and in vivo ADR were rarely performed, neither the covalent binding of toxic metabolites to endogenous macromolecules; let alone the preventing strategies on avoiding or eliminating ADR. In our previous work, we investigated thoroughly the human metabolism and pharmacokinetics of NBP. We also illuminated the mechanism underlying the hepatocyte toxicity of NBP, i.e., metabolic bioactivation of NBP was mediated via sulfation of its major metabolite 3-OH-NBP. Based on previous work, we will focus on NBP, tolcapone and lamotrigine and investigate the role of sulfation in the metabolic bioactivation of tolcapone and lamotrigine which may form resonant structures after sulfate cleavage, elucidate the relationship between in vitro metabolic bioactivation and in vivo ADR, explore the covalent binding scenario of toxic metabolites to endogenous macromolecules, and investigate the usefulness of preventing strategies in rats by means of introducing competing pathway. These basic research will significantly help avoid or eliminate ADR and provide robust scientific evidences for drug safety in clinical practice.

硫酸结合是重要的II相代谢反应，通常为解毒途径。近年来，不时有文献报道硫酸结合途径介导药物的不良反应，包括他莫昔芬的肝毒性和遗传毒性、奈韦拉平的严重皮疹、丁苯酞的中等肝毒性等。但是，相关的致毒分子机制研究仅局限于体外的代谢活化，且与体内毒性的相关性少有研究，毒性代谢物与体内大分子的共价结合情形也少有研究，更缺乏相应的预防策略研究。前期，我们系统研究了丁苯酞的人体代谢和药动学，并从体外阐明了代谢物3-羟基-丁苯酞的硫酸结合途径介导其肝细胞毒性的机理。基于前期工作，我们将以丁苯酞、托卡朋和拉莫三嗪为研究对象，深入研究硫酸结合途径与硫酸基团离去后可形成共振结构式的药物体外代谢活化的关系，阐明体外的代谢活化与体内毒性的相关性，探索毒性代谢物与体内蛋白质共价结合的情形，并在大鼠体内研究竞争性途径预防不良反应的有效性，这将极大地减弱或避免不良反应，为临床安全用药提供强有力的科学依据。

硫酸结合是重要的II相代谢反应，通常为解毒途径。近年来，不时有文献报道硫酸结合途径介导药物的不良反应，包括他莫昔芬的肝毒性和遗传毒性、奈韦拉平的严重皮疹、丁苯酞的中等肝毒性等。但是，相关的致毒分子机制研究仅局限于体外的代谢活化，且与体内毒性的相关性少有研究，毒性代谢物与体内大分子的共价结合情形也少有研究，更缺乏相应的预防策略研究。本项目中，我们系统研究了丁苯酞的吸收、分布、代谢、排泄，并从体外阐明了代谢物3-羟基-丁苯酞的硫酸结合途径介导其肝细胞毒性的机理。基于此，我们以丁苯酞、托卡朋和拉莫三嗪为研究对象，深入研究硫酸结合途径与硫酸基团离去后可形成共振结构式的药物体外代谢活化的关系，阐明体外的代谢活化与体内毒性的相关性，探索发现毒性代谢物与体内蛋白质共价结合，并在大鼠体内研究外源性补充谷胱甘肽可以预防丁苯酞的肝毒性，这将极大地减弱或避免不良反应，为临床安全用药提供强有力的科学依据。