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）：由于多种药物治疗的广泛流行，药物间相互作用在临床不良事件中起着重要作用。最近已证明人细胞色素P450 4F（CYP 4F）亚家族酶在内源性化合物（包括花生四烯酸和白三烯B4（LTB 4））和药物/营养素（包括帕呋脒、芬戈莫德和维生素E）的代谢中发挥重要作用。然而，CYP 4F酶在介导潜在药物相互作用中的作用仍不明确。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已报告了许多具有临床意义的不良相互作用，包括严重和致死性出血事件。预计这些药物的联合给药将增加，部分原因是他汀类药物的多效性作用。深入了解他汀类药物与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与华法林联合用药提供必要的科学依据和方法，并允许制定相关的监管措施，限制每年数十万人使用某些高风险的他汀类药物与华法林联合用药，这具有重要的公共卫生意义。PI研究计划的长期目标是进一步了解人CYP 4F酶的药理学和生理学作用。拟议研究的具体目标是对CYP 4F 2在他汀类药物和华法林相互作用中的作用进行机制性理解。将采用一种创新和转化的实验方法来检验中心假设，即某些他汀类药物诱导CYP 4F 2介导的维生素K1代谢并增强华法林在人体中的抗凝作用。新方法学，包括用于蛋白质定量的基于质谱（MS）的定量蛋白质组学方法、CYP 4F 2的标记底物活性测定和双盲、随机、安慰剂对照、2阶段交叉临床研究，将用于解决以下关键问题：1）维生素K1在？- CYP 4F 2羟基化; 2）他汀类药物治疗对CYP 4F 2蛋白表达和酶活性的诱导; 3）他汀类药物对华法林抗凝疗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理解CYP 4F酶的药理学和生理学作用的基础，并将提供用于开发更安全的他汀类药物的重要信息，以及一种机制，通过该机制，可根据其CYP 4F 2诱导潜力对已批准的他汀类药物进行排序，以指导伴随给药时华法林的剂量调整。本研究的主要目的是：1）鉴定和表征维生素K1的代谢产物（K1-？- OH）; 2）确定他汀类药物对HepG 2细胞和原代人肝细胞中CYP 4F 2的诱导特征; 3）评估他汀类药物治疗对健康志愿者中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，药物相互作用在临床不良事件中起着重要作用。尽管有大量临床显著不良相互作用的报告，但华法林和他汀类药物的联合用药在过去几十年中在美国急剧扩大。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。