DEFECTS OF DRUG METABOLISM IN LABORATORY ANIMALS

简介(改编自申请人的摘要)：建议 研究将使用生化和分子遗传技术来 阐明药物中常见但知之甚少的缺陷 新陈代谢是特定物种、品种和 实验动物品系。这个项目的主要关注点是 葡萄糖醛酸化反应。这一知识不仅对人类健康很重要 从提高效果的可预见性方面来说 药物在人类疾病的动物模型中的应用，例如猫，也许 在临床前药物试验中，还因为这样的动物可能 药物葡萄糖醛酸化缺乏症的相似分子基础模型 某些病人。临床上，葡萄糖酸化反应异常 部分原因是对乙酰氨基酚[Tylenol(R)]的毒性显著增强 和乙酰水杨酸(阿司匹林)在猫与其他 物种。在人类中也观察到了类似的葡萄糖醛酸化缺陷 Crigler-Najjar综合征和Gilbert综合征(一种疾病)的患者 据估计，这将影响5%-7%的人口)。为了支持这一点 研究重点，该实验室的初步数据表明， CAT缺乏UDP的一个亚型的显著表达- Crigler-Najjar综合征患者的葡萄糖醛酸基转移酶缺陷 可能还有吉尔伯特综合症。

DESCRIPTION (Adapted from the applicant's abstract): The proposed research will use biochemical and molecular genetic techniques to elucidate commonly known, but poorly understood, defects in drug metabolism that are characteristic of particular species, breeds and strains of laboratory animals. The primary focus of this project is on glucuronidation. This knowledge is important to human health not only from the aspect that it will improve the predictability of the effects of drugs in animal models of human disease, such as the cat, and perhaps in preclinical pharmaceutical testing, but also because such animals may model similar molecular bases for drug glucuronidation deficiency in certain patients. Clinically, abnormalities in glucoronidation accounts in part for significantly enhanced toxicity of acetaminophen [Tylenol(R)] and acetylsalicylic acid (aspirin) in the cat compared with other species. Similar glucuronidation deficits have been observed in human patients with Crigler-Najjar syndrome and Gilbert's syndrome (a disease that is estimated to affect 5-7% of the population). In support of this research focus, preliminary data from this laboratory suggests that the cat lacks significant expression of one isoform of UDP- glucuronyltransferase shown to be defective in Crigler-Najjar syndrome and possibly Gilbert's syndrome.