DISPOSITION OF ACYL GLUCURONIDES & THEIR PROTEIN ADDUCTS

药物、其他外来生物物质和含有 无处不在的羧酸官能团通常被 与葡萄糖醛酸偶联制得酰基(酯连接) 葡萄糖醛酸苷。现在有充分的证据证明，这种代谢物可以到达 血液中可察觉到的浓度是不稳定的，经历了pH依赖 葡萄糖醛酸异构体的分子内酰基迁移 或水解，并可能与血浆或组织蛋白发生不可逆转的反应， 在体外和体内都有。目前，科学家们都很清楚 酰基葡萄糖醛酸类化合物的不稳定性及其共价反应潜力 与蛋白质及其与毒性的假设联系，通过 明显的免疫不良反应或通过修改临界 蛋白质。对这一现象的更好理解可能会导致新的 开发出不良反应较少的药物。药物代谢为酰基 葡萄糖醛酸苷仍被认为具有不可接受的毒性，因为 表现在1988年美国停用舒洛芬和 酮咯酸于1994年从德国和法国市场上市。酰基的反应 葡萄糖醛酸苷和蛋白质似乎是通过两种机制中的一种， 酰基迁移后的亲核取代和亚胺的形成， 尽管在体内哪个更具优势或毒理意义 没有得到解决。直到最近，还没有因果关系。 酰基形成的共价加合物之间的关系 葡萄糖醛酸苷和毒性；也没有任何不良反应的动物模型 由酰基葡萄糖醛酸苷引起的反应。然而，最近一段关系 酰基葡萄糖醛酸化物的形成速度、不稳定性和观察值之间的关系 苯甘氨酸对小鼠和大鼠的肝胆毒性 据报道，作为药物正在开发中。这一系列苯基羧酸 ACID提供了一个系统研究潜在机制的机会 用于酰基葡萄糖醛酸苷介导的毒性。 这些考虑表明，对人格特质的持续研究 而酰基葡萄糖醛酸苷的反应性是有保证的，并导致 以下研究问题：1.共价元素之间是否存在相关性 酸性化合物与蛋白质结合的体内外观察 代谢成酰基葡萄糖醛酸苷的酸的毒性？；和2。 对酰基葡萄糖醛酸苷的反应性可以通过理解 这些酸性化合物的化学组成及其作用机理 与蛋白质结合？这些问题将通过一个 一系列协调的体外实验和小动物研究 活性和稳定性的酰基葡萄糖醛酸苷以及通过计算 对所涉及的化学过程进行建模。

Drugs, other xenobiotics and endogenous compounds that contain the ubiquitous carboxylic acid functional group are often metabolized by conjugation with glucuronic acid to form acyl (ester linked) glucuronides. It is now well documented that such metabolites can reach appreciable concentrations in blood, are labile, undergoing pH-dependent intramolecular acyl migration to isomeric conjugates of glucuronic acid or hydrolysis and may react irreversibly with plasma or tissue proteins, both in vitro and in vivo. Currently scientists are well aware of the instability of acyl glucuronides, their potential to react covalently with proteins and their postulated link with toxicity, through either apparent untoward immunological responses or by modification of critical proteins. A better understanding of the phenomenon may lead to newly developed drugs with less adverse reactions. Drugs metabolized to acyl glucuronides are still being identified to have unacceptable toxicity as shown by the withdrawal of suprofen in the U.S. in 1988 and that of ketorolac from German and French market in 1994. The reaction of acyl glucuronides with proteins appears to be by either of two mechanisms, nucleophilic displacement and imine formation after acyl migration, though which is more dominant or toxicologically significant in vivo has not been resolved. Until recently, there was no cause-effect relationship established between covalent adducts formed by acyl glucuronides and toxicity; nor was there an animal model for any adverse reactions due to acyl glucuronides. However, recently a relationship between acyl glucuronide formation rates, instability and observed hepatobiliary toxicity in mice and rats for a sense of phenyl glycines under development as drugs was reported. This series of phenyl carboxylic acid offers an opportunity to systematically study potential mechanisms for acyl glucuronide mediated toxicity. These considerations indicate that continued research on the disposition and reactivity of acyl glucuronides is warranted and lead to the following research questions: 1. Is there a correlation between covalent binding of acidic compounds to proteins in vivo or in vitro and observed toxicity for acids metabolized to acyl glucuronides?; and 2. Can the reactivity of acyl glucuronides be predicted by understanding of the chemistry of these acidic compounds and the mechanisms involved in their binding to proteins? These questions will be addressed through a coordinated series of in vitro experiments and small animal studies using reactive and stable acyl glucuronides as well as by computational modeling of the chemical processes involved.