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Toxicological importance of CYP3A4 catalysis and inhibition

CYP3A4 催化和抑制的毒理学重要性

基本信息

批准号：
9275987
负责人：
Irina F Sevrioukova
金额：
$ 34.76万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-01 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9275987
关键词：
Active Sites Address Affect Affinity Agriculture Allosteric Regulation Area Attenuated Behavior Binding Binding Sites Biochemical CYP3A4 gene Carcinogens Catalysis Cessation of life Chemical Structure Chemicals Clinical Trials Complex Consumption Crystallization Cytochrome P450 Data Development Diet Dietary Flavonoid Docking Drug Interactions Drug toxicity Environmental Pollutants Enzymes Exhibits Failure Flavonoids Goals HIV Infections Health Hepatitis C Herbicides Human Insecticides Investigation Kinetics Knowledge Lead Ligand Binding Light Maps Metabolism Modeling Molecular Conformation NADP Occupations Peripheral Pesticides Pharmaceutical Preparations Pharmacologic Substance Plants Play Prevention Process Progesterone Protein Dynamics Protein Isoforms Public Health Quantitative Structure-Activity Relationship Research Ritonavir Roentgen Rays Role Site Structure Substrate Specificity Surface Testing Time Toxic effect Toxicology Withdrawal Xenobiotic Metabolism Xenobiotics analog base biophysical techniques clinically relevant design drug development drug efficacy drug metabolism environmental chemical in vivo inhibitor/antagonist insight inter-individual variation novel oxidation pharmacophore public health relevance stoichiometry

项目摘要

DESCRIPTION (provided by applicant): Human cytochrome P450 3A4 (CYP3A4) is the most abundant and clinically relevant xenobiotic-metabolizing P450 in humans and is well known for its extreme promiscuity in substrate specificity and allosteric behavior. In addition to the metabolism of drugs and endogenous compounds, CYP3A4 is implicated in oxidation and bioactivation of pesticides, insecticides, herbicides, carcinogens and environmental pollutants. CYP3A4 can also be inhibited and activated by xenobiotics, which may lead to undesired drug-drug interactions, toxicity and human death. Despite the central role of CYP3A4 in drug metabolism, its mechanism of inhibition and activation are still poorly understood. This proposal is designed to address key issues in both areas of the CYP3A4 research and centers on our advances in the structural and functional investigation of the CYP3A4- ligand binding process. The goal of Aim 1 is to optimize the CYP3A4 inhibitor pharmacophore model that was built based on our studies of analogs of ritonavir, the most potent pharmacoenhancer marketed to date. We will accurately identify the pharmacophoric determinants using novel, rationally designed compounds, which will be further optimized based on structural and functional interpretations. The structure-based CYP3A4-specific inhibitor pharmacophore could assist in identification and early elimination of potential CYP3A4 inactivators during development of drugs and other chemicals used in agriculture and public health, as well as designing more potent pharmacoenhancers. The second part of the proposal focuses on the allosteric behavior of CYP3A4, thought to arise from the multiple substrate binding. CYP3A4 can be activated by various xenobiotics and natural dietary compounds, such as plant flavonoids, but the underlying mechanism is still under debate. Our recent findings suggest that the substrate-access channel rather than the previously identified peripheral area serves as a high affinity effector binding sie. The goal of Aim 2 is to test this hypothesis by comparing the relative importance of the peripheral and intra-channel sites in the CYP3A4 activation by flavonoid-like molecules. Using an integrated structural, biochemical and biophysical approach, we will assess how disruption of these areas affects protein dynamics, substrate binding stoichiometry, kinetics and metabolism. These studies will provide novel insights into the mechanism of CYP3A4 activation, substrate cooperativity and drug-drug interactions, which is essential for prediction/prevention of chemical toxicity and understanding interindividual differences in metabolism of drugs, dietary compounds and environmental chemicals.