CHEMOPREVENTIVE AGENTS AND HUMAN CYTOCHROME P450 IN VIVO

癌症的发展通常涉及环境因素， 因此，预防战略是一项特别重要的战略， 降低癌症风险的有吸引力的方法。为此，各种 假定的化学预防剂或者处于临床前 研究、药物开发或临床评价。 的 这些代理人的理由是基于这样的概念，大多数 环境（亲）致癌物本身是无活性的，需要代谢 这一过程与后续的平衡， 在个体对癌症的易感性中， 过程 因此，减少适当的阶段I激活 酶和/或增加一个重要的第二阶段解毒酶可以 降低癌症风险。 然而，由于这种调制不太可能 如果仅限于单一酶或系统， 交互可能比先前所想的或期望的要少。 的 细胞色素P450（CYP）系统在这方面尤为重要 因为它在原致癌物活化中通常是关键的， 酶在药物代谢中也非常重要。因此，委员会认为， 施用化学预防剂不仅可以改变癌症 风险和药物疗效。 拟议研究的目标， 因此，确定选择的化学预防剂的效果， 药物对健康人体内特异性β-内酰胺酶活性的影响 科目 待研究的药物是奥替普拉， 苯乙基异硫氰酸酯和S-烯丙基半胱氨酸，其具有 成为或即将用于临床研究。 的 一种实验方法将基于一种传统的药物 使用选定的体内探针进行相互作用研究设计，反映 单个β-同种型的活性，以确定 单次和重复给药的抑制和/或诱导作用 化学预防剂对探针代谢的影响。 的β亚型 感兴趣的和相关的体内探针是CYP 1A 2（咖啡因）， CYP 2A 6（香豆素）、CYP 2C 9（甲苯磺丁脲）、CYP 2C 19（美芬妥英）、CYP 2D 6 （异喹胍）、CYP 2 E1（氯唑沙宗）和CYP 3A（咪达唑仑）。 的 由此产生的数据将首次提供有关此类信息， 人类体内的相互作用-最终模型-而不是 动物和/或体外制备。此外，信息将 在进一步开发和评价有效性/ 这些新化学预防剂的毒性。

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.