Inter-Enzyme Crosstalk in the Cytochrome P450 Ensemble: Implications for the Effects of Alcohol on Drug Metabolism and Alcohol-Drug Interactions

细胞色素 P450 整体中的酶间串扰：酒精对药物代谢和酒精-药物相互作用影响的影响

• 批准号: 10704053
• 负责人: Dmitri R Davydov
• 金额: $ 50.08万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-13 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10704053
• 关键词: AODR mortality; Adverse drug effect; Adverse effects; Affect; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcohol-Induced Disorders; Alcohols; Biological Assay; CYP1A2 gene; CYP2C19 gene; CYP2C9 gene; CYP2D6 gene; CYP2E1 gene; CYP3A4 gene; Chemicals; Chronic; Clinical; Cocaine; Collection; Complex; Cytochrome P450; Diazepam; Drug Interactions; Drug Kinetics; Drug Metabolism Induction; Drug Prescriptions; Drug usage; Eicosanoids; Endoplasmic Reticulum; Enzyme Induction; Enzymes; Foundations; Genotype; Goals; Health; Hepatocyte; Human; Hypertension; Individual; Knowledge; Knowledge acquisition; Life; Liver; Liver Microsomes; Mass Spectrum Analysis; Mediating; Medical; Membrane; Metabolic; Metabolism; Minor; Opioid; Pathogenesis; Pharmaceutical Preparations; Phenytoin; Physiological; Play; Preparation; Prevention; Property; Proteins; Proteomics; Public Health; Recording of previous events; Regulation; Research; Role; Route; Series; Signal Pathway; Signal Transduction; Substrate Specificity; System; Systems Integration; Therapeutic; Tissues; Tolbutamide; Tretinoin; Warfarin; alcohol abuse therapy; alcohol effect; alcohol exposure; alcohol use disorder; carcinogenesis; crosslink; drug metabolism; drug of abuse; high throughput screening; insight; intermolecular interaction; interspecies communication; pharmacokinetics and pharmacodynamics; pharmacologic; protein expression; protein protein interaction

The effect of alcohol consumption on drug metabolism and interactions of alcohol with drugs constitute a significant health problem. The mechanisms of these effects are tightly related to the influence of alcohol on drug- metabolizing system, and on cytochrome P450 ensemble in particular. Functional versatility of the cytochrome P450 system is achieved through the presence of over a dozen of P450 species differing in their substrate specificity. The composition of this ensemble is known to be largely affected by alcohol consumption. It is generally presumed that the integral properties of this ensemble represent a simple aggregate of the properties of the constituting P450 enzymes. Although this premise remains to be a foundation of rational analysis of the routes of drug metabolism, its validity became essentially compromised. The body of evidence of system-wide integration in the properties of the P450 ensemble continues to grow. The current project is prompted by recognition of a far-reaching physiological significance and pharmacological importance of inter-species crosstalk in the P450 ensemble and its thorough relevance to the effects of alcohol on drug metabolism and P450- dependent cellular signaling. Our central hypothesis is that the results of the alcohol-induced changes in the composition of the cytochrome P450 pool are not limited to direct consequences of the activity of the alcohol-induced enzymes. They also involve alterations of the metabolism of a broad range of exogenous and endogenous substrates of various P450 enzymes due to their interactions with alcohol-inducible P450 species. These indirect effects are deeply involved in clinically-important cases of alcohol interactions with drugs and alcohol-induced alteration of cellular signaling through eicosanoids, retinoic acid and other P450-dependent messengers. This proposal is aimed to explore the alcohol-induced changes in P450 expression and their effects of on the network of protein-protein interaction in the ER membranes and, consequently, on the system-wide properties of the P450 ensemble. Our long-term goal is to obtain a complete picture of functional interactions between human cytochromes P450, and the alcohol-inducible P450 species in particular, and characterize their role in dictating the integral properties of the drug-metabolizing ensemble and their changes by alcohol consumption. Specific Aims of the project are: (1) To refine our knowledge on alcohol-induced changes in the composition of the cytochrome P450 ensemble in liver cells; (2) To identify the principal intermolecular interactions of alcohol- induced P450 species in HLM; (3) To identify the major functional interactions of alcohol-inducible P450 enzymes with other P450 species and explore their effect on the metabolism of drugs and endogenous substrates by the P450 ensemble. Fulfilling these aims will allow in-depth characterization of alcohol-induced changes in drug-metabolism and P450-dependent cellular signaling and understand their role in deleterious alcohol-drug interactions and other adverse effects of alcohol consumption.

饮酒对药物代谢的影响以及酒精与药物的相互作用构成了一个新的研究领域。 严重的健康问题。这些作用的机制与酒精对药物的影响密切相关， 代谢系统，特别是细胞色素P450系综。细胞色素的功能多样性 P450系统是通过存在十几种不同底物的P450物质来实现的 的特异性众所周知，这一群体的组成在很大程度上受到酒精消费的影响。是 一般认为，该系综的整体性质代表了性质的简单集合 组成P450酶。虽然这一前提仍然是理性分析的基础， 药物代谢途径，其有效性基本上受到损害。全系统的证据主体 P450系综的特性的集成继续增长。当前项目的提示是 认识到种间串扰的深远生理意义和药理学重要性 在P450整体及其彻底的相关性，酒精对药物代谢和P450的影响， 依赖细胞信号传导。 我们的中心假设是，酒精引起的细胞色素组成变化的结果， P450库不限于酒精诱导的酶的活性的直接后果。他们还 涉及各种P450的广泛的外源性和内源性底物的代谢的改变 酶，因为它们与酒精诱导的P450物种的相互作用。这些间接的影响是深层次的 在酒精与药物相互作用和酒精诱导的细胞凋亡的临床重要病例中， 通过类花生酸、视黄酸和其他依赖P450的信使进行信号传导。 本研究旨在探讨酒精诱导的P450表达的变化及其对神经细胞凋亡的影响。 蛋白质-蛋白质相互作用的网络在ER膜，因此，对系统范围的性质 P450系列我们的长期目标是获得一个完整的图片之间的功能相互作用 人细胞色素P450，特别是酒精诱导的P450种类，并表征它们在 指示药物代谢集合体的整体性质及其通过酒精消耗的变化。 本项目的具体目标是：（1）完善我们对酒精引起的组成变化的认识， 肝细胞中细胞色素P450系综;（2）确定乙醇- （3）确定酒精诱导的P450在HLM中的主要功能相互作用 酶与其他P450物种，并探讨其对药物和内源性底物代谢的影响 P450系列实现这些目标将使我们能够深入描述酒精引起的变化， 药物代谢和P450依赖的细胞信号传导，并了解它们在有害的酒精药物代谢中的作用 酒精消费的相互作用和其他不利影响。

项目成果

High-Throughput Assay of Cytochrome P450-Dependent Drug Demethylation Reactions and Its Use to Re-Evaluate the Pathways of Ketamine Metabolism.

• DOI: 10.3390/biology12081055
• 发表时间: 2023-07-27
• 期刊: Biology
• 影响因子: 4.2