Human Cytochrome P450 4F Enzymes and Drug Interactions

人类细胞色素 P450 4F 酶和药物相互作用

• 批准号: 8469669
• 负责人: Zhuo Michael Wang
• 金额: $ 21.16万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-06 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8469669
• 关键词: Human; Cytochrome; P450; 4F; Enzymes

DESCRIPTION (provided by applicant): Drug-drug interactions play an important role in clinical adverse events due to the wide prevalence of multi-drug therapies. The human cytochrome P450 4F (CYP4F) subfamily of enzymes has recently been demonstrated to play a significant role in the metabolism of both endogenous compounds, including arachidonic acid and leukotrienes B4 (LTB4), and drugs/nutrients, including pafuramidine, fingolimod, and vitamin E. However, the role of CYP4F enzymes in mediating potential drug interactions remains uncharacterized. Numerous clinically significant adverse interactions, including major and fatal bleeding episodes, have been reported between the widely-prescribed cholesterol-lowering agents, the "statins", and the anticoagulant warfarin. Co-administration of these drugs is expected to be on the rise due in part to the purported pleiotropic effects of statins. An improved understanding of the molecular mechanisms underlying the statin-warfarin interaction will provide necessary scientific basis and methodologies to develop an interaction-free statin-warfarin combination, and allow enactment of pertinent regulatory measures limiting certain high-risk statin-warfarin combinations to be prescribed to hundreds of thousands of people each year, which has great public health importance. The long-term goal of the PI's research program is to further our understanding of the pharmacologic and physiologic role of the human CYP4F enzymes. The specific goal of the proposed research is to develop a mechanistic understanding of the role of CYP4F2 in the interaction between statins and warfarin. An innovative and translational experimental approach will be employed to test the central hypothesis that certain statins induce CYP4F2-mediated vitamin K1 metabolism and potentiate the anticoagulant effect of warfarin in humans. Novel methodologies, including a mass spectrometry (MS)-based quantitative proteomic approach for protein quantification, a marker substrate activity assay for CYP4F2, and a double-blind, randomized, placebo-controlled, 2-period cross-over clinical study will be utilized to address key issues regarding 1) the deactivation of vitamin K1 upon ?-hydroxylation by CYP4F2; 2) the induction of CYP4F2 protein expression and enzymatic activity by statin treatment; and 3) the clinical relevance of the effect of statins on warfarin anticoagulation efficacy. Results obtained from the proposed translational research will serve as a foundation for understanding the pharmacologic and physiologic role of CYP4F enzymes, and will provide important information useful in the development of safer statins, and a mechanism by which approved statins can be rank-ordered according to their CYP4F2-inducing potential to guide warfarin dosage adjustment when administered concomitantly. The proposed work has the following specific aims: 1) identify and characterize the vitamin K1 metabolite (K1-?-OH) generated by CYP4F2; 2) determine the induction profiles of statins towards CYP4F2 in HepG2 cells and primary human hepatocytes; and 3) assess the influence of statin treatment on the anticoagulant effect of warfarin in healthy volunteers. PUBLIC HEALTH RELEVANCE: Drug-drug interactions play an important role in clinical adverse events due to the wide prevalence of multi-drug therapy. In spite of numerous reports of clinically significant adverse interactions, the co-medication of warfarin and statins has drastically expanded in the US over the last decades. This proposal seeks to demonstrate a novel molecular mechanism for the statin-warfarin interaction and provide a pathway to develop an interaction-free statin-warfarin combination.

描述（由申请人提供）：由于多种药物疗法的广泛流行，药物间相互作用在临床不良事件中发挥着重要作用。最近已证明人细胞色素 P450 4F (CYP4F) 酶亚家族在内源性化合物（包括花生四烯酸和白三烯 B4 (LTB4)）以及药物/营养素（包括帕呋拉明、芬戈莫德和维生素 E）的代谢中发挥着重要作用。然而，CYP4F 酶在介导电位中的作用 药物相互作用仍然未知。据报道，广泛使用的降胆固醇药物“他汀类药物”和抗凝剂华法林之间存在许多临床上显着的不良相互作用，包括严重和致命的出血事件。预计这些药物的联合用药将会增加，部分原因是他汀类药物据称具有多效性。更好地了解他汀类药物-华法林相互作用的分子机制将为开发无相互作用的他汀类药物-华法林组合提供必要的科学基础和方法，并允许制定相关监管措施，限制每年向数十万人开具的某些高风险他汀类药物-华法林组合，这对公共卫生具有重要意义。 PI 研究计划的长期目标是进一步了解人类 CYP4F 酶的药理学和生理作用。本研究的具体目标是从机制上理解 CYP4F2 在他汀类药物和华法林相互作用中的作用。将采用创新的转化实验方法来测试中心假设，即某些他汀类药物可诱导 CYP4F2 介导的维生素 K1 代谢并增强华法林在人体中的抗凝作用。新颖的方法，包括基于质谱 (MS) 的蛋白质定量方法、CYP4F2 的标记底物活性测定以及双盲、随机、安慰剂对照、2 期交叉临床研究，将用于解决以下关键问题：1) CYP4F2 α-羟基化后维生素 K1 失活； 2)通过他汀类药物治疗诱导CYP4F2蛋白表达和酶活性； 3）他汀类药物对华法林抗凝功效影响的临床相关性。从拟议的转化研究中获得的结果将作为了解 CYP4F 酶的药理和生理作用的基础，并将为开发更安全的他汀类药物提供有用的重要信息，并提供一种机制，通过这种机制，批准的他汀类药物可以根据其 CYP4F2 诱导潜力进行排序，以指导同时服用时的华法林剂量调整。拟议的工作有以下具体目标：1）识别和表征CYP4F2产生的维生素K1代谢物（K1-α-OH）； 2)确定他汀类药物对HepG2细胞和原代人肝细胞中CYP4F2的诱导曲线； 3) 评估健康志愿者中他汀类药物治疗对华法林抗凝作用的影响。 公共卫生相关性：由于多种药物治疗的广泛流行，药物间相互作用在临床不良事件中发挥着重要作用。尽管有大量关于临床上显着不良相互作用的报道，但华法林和他汀类药物的联合用药在过去几十年来在美国急剧扩大。该提案旨在证明他汀类药物-华法林相互作用的新分子机制，并提供开发无相互作用的他汀类药物-华法林组合的途径。