DEFECTS OF DRUG METABOLISM IN LABORATORY ANIMALS

描述（改编自申请人摘要）：拟定的 研究将使用生物化学和分子遗传技术， 阐明药物中众所周知但知之甚少的缺陷 特定物种、品种和 实验室动物的品种。该项目的主要重点是 葡萄糖醛酸化。 这些知识不仅对人类健康很重要， 从它将提高效果的可预测性的方面来看， 在人类疾病的动物模型中，比如猫， 在临床前药物测试中，也因为这些动物可能 药物葡萄糖醛酸化缺陷的模型相似分子基础 某些病人。 临床上，葡萄糖醛酸化异常 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）在猫与其他相比， 物种 在人体中观察到类似的葡萄糖醛酸化缺陷 患有Crigler-Najjar综合征和吉尔伯特综合征（一种疾病 据估计，这将影响5-7%的人口）。 为支持这一 研究重点，该实验室的初步数据表明， 猫缺乏一种UDP亚型的显著表达， 葡萄糖醛酸转移酶在Crigler-Najjar综合征中存在缺陷 可能还有吉尔伯特综合征

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.