Enzymology of xenobiotic metabolism

外源物质代谢的酶学

• 批准号: 2537-2012
• 负责人: Josephy, David
• 金额: $ 1.89万
• 依托单位: University of Guelph
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2015
• 资助国家: 加拿大
• 起止时间: 2015-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=568250
• 关键词: Enzymology; xenobiotic; metabolism

Foreign chemicals, such as pollutants, drugs, and other toxicants, are metabolized (i.e., chemically modified, prior to elimination) in the human body. This process of metabolism, catalyzed by enzymes in the liver and other organs, is the main determinant of the rate at which a drug is eliminated from the body; this, in turn, influences the effectiveness and toxicity of the drug. . Rates of drug metabolism vary widely among individuals, and genetic factors are an important source of this variation, which can have major effects on response to drug therapy. When treated with standard doses, "poor metabolizers" may be at risk of overdose toxicity while "ultrarapid metabolizers" fail to receive therapeutic benefit. With some drugs, metabolism may generate an active agent, and so the opposite scenario applies: ultrarapid metabolizers risk overdose. The completion of the human genome and subsequent spectacular improvements in DNA sequencing technology have recently provided deep new insight into genetic variations in the enzymes of drug metabolism. Also, genomic analysis has revealed the existence of previously unknown genes and enzymes. The focus of research in the Josephy lab is the analysis of the functional effects of human genetic variation in drug and toxicant metabolism enzymes, including the glutathione transferase and cytochrome P450 families of enzymes.

外来化学物质，如污染物、药物和其他有毒物质，被代谢（即，化学修饰，在消除之前）在人体内。这种代谢过程由肝脏和其他器官中的酶催化，是药物从体内消除速率的主要决定因素;这反过来又影响药物的有效性和毒性。.药物代谢速率在个体之间差异很大，遗传因素是这种差异的重要来源，这可能对药物治疗的反应产生重大影响。当用标准剂量治疗时，“弱代谢者”可能有过量毒性的风险，而“超速代谢者”则无法获得治疗益处。对于某些药物，代谢可能会产生活性剂，因此相反的情况适用：超快速代谢者有过量的风险。 人类基因组的完成和随后DNA测序技术的惊人改进，最近为药物代谢酶的遗传变异提供了新的深刻见解。此外，基因组分析揭示了以前未知的基因和酶的存在。Josephy实验室的研究重点是分析人类遗传变异对药物和毒物代谢酶（包括谷胱甘肽转移酶和细胞色素P450酶家族）的功能影响。