CHEMOPREVENTIVE AGENTS AND HUMAN CYTOCHROME P450 IN VIVO

体内化学预防剂和人细胞色素 P450

• 批准号: 6342049
• 负责人: grant R. wilkinson
• 金额: $ 27.42万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-01-01 至 2002-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6342049
• 关键词: alpha benzopyrone; antineoplastics; caffeine; cancer prevention; chemoprevention; clinical research; cysteine; cytochrome P450; debrisoquin; detoxification; dosage; drug interactions; human subject; isothiocyanates; isozymes; midazolam; neoplasm /cancer pharmacology; oltipraz; pharmacokinetics; phenytoin; tolbutamide

The development of cancer frequently involves an environmental component(s) and for this reason a prevention strategy is a particularly attractive approach for reducing cancer risk. To this end, various putative chemopreventive agents are either under preclinical investigation, development as drugs, or clinical evaluation. The rationale of certain of these agents is based on the notion that most environmental (pro)carcinogens are inactive per se and require metabolic activation, and that the balance between this process and subsequent elimination is important in an individual's susceptibility to the cancer process. Accordingly, decreasing an appropriate Phase I activating enzyme and/or increasing an important Phase II detoxifying enzyme could reduce cancer risk. However, because such modulation is not likely to be limited to a single enzyme or system, the selectivity of the interaction may be less than previously thought or desired. The cytochrome P450 (CYP) system is particularly important in this regard because it is often critical in procarcinogen activation, and these enzymes are also very important in the metabolism of drugs. Accordingly, the administration of a chemopreventive agent may not only alter cancer risk but also drug efficacy. The goal of the proposed research, therefore, is to determine the effects of selected chemopreventive agents on the in vivo activity of specific CYP enzymes in healthy human subjects. The agents to be studied are oltipraz, phenethylisothiocyanate and S-allylcysteine, which have either just become, or are about to be available for clinical investigation. The proposed experimental approach will be based on a conventional drug interaction study design using selected in vivo probes, reflective of the activity of individual CYP isoforms, in order to determine the inhibitory and/or inductive effects of single and repeated doses of the chemopreventive agent on the probes metabolism. The CYP isoforms of interest and the associated in vivo probes will be CYP1A2 (caffeine), CYP2A6 (coumarin), CYP2C9 (tolbutamide), CYP2C19 (mephenytoin), CYP2D6 (debrisoquine), CYP2E1(chlorzoxazone) and CYP3A(midazolam). The resulting data will provide, for the first time, information about such interactions in vivo in humans - the ultimate model -rather than in animals and/or in in vitro preparations. Moreover, the information will be of value in the further development and evaluation of the efficacy/ toxicity of these new chemopreventive agent.

癌症的发展常常与环境因素有关。 组成部分(S)，因此，预防战略是一个特别 降低癌症风险的有吸引力的方法。为此，各种 可能的化学预防药物要么处于临床前阶段 作为药物的研究、开发或临床评价。这个 其中某些代理人的理论基础是基于这样一个概念，即大多数 环境致癌物质本身是不活跃的，需要新陈代谢 激活，以及这个过程和随后的平衡 消除对个人患癌症的易感性是很重要的 进程。因此，减少适当的阶段I激活 酶和/或增加一种重要的II相解毒酶可以 降低癌症风险。然而，因为这种调制不太可能 限于单一的酶或体系，其选择性 互动可能比之前认为或期望的要少。这个 细胞色素P450(CYP)系统在这方面尤为重要 因为它通常是致癌原激活的关键，而这些 酶在药物的新陈代谢中也非常重要。因此， 使用化学预防药物不仅可以改变癌症 不仅有风险，而且还有药效。拟议研究的目标是， 因此，确定选定的化学预防措施的效果 健康人体内特异性CYP酶活性的研究进展 研究对象。被研究的药物是奥替拉兹， 苯乙基异硫氰酸酯和S-烯丙基半胱氨酸 成为或即将可用于临床研究。这个 拟议的实验方法将基于一种传统药物 使用精选的体内探针进行交互研究设计，反映 单个CYP亚型的活性，以确定 单次和多次给药的抑制和/或诱导作用 化学防腐剂对探针代谢的影响。CYP的异构体 感兴趣的和相关的体内探针将是CYP1A2(咖啡因)， CYP2A6(香豆素)、CYP2C9(甲苯丁胺)、CYP2C19(美苯妥英)、CYP2D6 (Debrisquine)、CYP2E1(氯唑沙宗)和CyP3A(咪达唑仑)。这个 由此产生的数据将第一次提供关于这种情况的信息 在人体内的相互作用--终极模型--而不是 动物和/或体外制剂中。此外，这些信息将 在进一步发展和评估疗效方面有价值 这些新的化学预防药物的毒性。