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.

癌症的发展经常涉及环境 组成部分，因此，预防策略是一个特别的 降低癌症风险的有吸引力的方法。为此，各种各样 推定的化学预防剂要么在临床前 研究，作为药物的发展或临床评估。 这 这些代理中的某些理由是基于大多数的观念 环境（Pro）致癌物本身不活跃，需要代谢 激活，以及此过程与随后的平衡 消除对于个人对癌症的敏感性很重要 过程。 因此，减少适当的I阶段激活 酶和/或增加重要的II期解毒酶可以 降低癌症风险。 但是，因为这样的调制不太可能 仅限于单个酶或系统， 相互作用可能比以前的想法要小。 这 细胞色素P450（CYP）系统在这方面尤为重要 因为它通常在procarcinogen激活中至关重要，而这些 酶在药物的代谢中也非常重要。因此， 化学预防剂的给药不仅可能改变癌症 风险，但也有吸毒功效。 拟议研究的目标， 因此，是确定选定的化学预防的影响 对健康人的特定CYP酶的体内活性的药物 主题。 要研究的特工是Oltipraz， 苯甲乙醇氰酸酯和s-甲甲甲酰半胱氨酸，它们要么仅 成为或即将进行临床研究。 这 建议的实验方法将基于常规药物 相互作用研究设计使用选定的体内探针，反映 单个CYP同工型的活性，以确定 单剂量和反复剂量的抑制性和/或诱导作用 探针代谢的化学预防剂。 CYP的同工型 兴趣和相关的体内探针将是CYP1A2（咖啡因）， CYP2A6（香豆素），CYP2C9（Tolbutamide），CYP2C19（Mephenytoin），CYP2D6 （碎屑），CYP2E1（Chlorzoxazone）和CYP3A（咪达唑仑）。 这 结果数据将首次提供有关此类的信息 人类体内的相互作用 - 最终模型 - 比起 动物和/或体外制剂。而且，信息将 在进一步发展和评估功效中具有价值 这些新化学预防剂的毒性。