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 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 整体。细胞色素的多功能性 P450 系统是通过十多种底物不同的 P450 物种实现的 特异性。众所周知，这个整体的组成很大程度上受到饮酒的影响。这是 通常假定该系综的整体属性代表属性的简单聚合 P450 酶的组成。尽管这个前提仍然是理性分析的基础 药物代谢途径的改变，其有效性基本上受到损害。全系统证据体系 P450 整体特性的集成度持续增长。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 整体中及其与酒精对药物代谢和 P450 的影响的彻底相关性 依赖的细胞信号传导。 我们的中心假设是酒精引起的细胞色素成分变化的结果 P450 池不限于酒精诱导酶活性的直接后果。他们还 涉及各种 P450 的多种外源性和内源性底物代谢的改变 由于它们与酒精诱导的 P450 物种相互作用而产生的酶。这些间接影响深入人心 在酒精与药物相互作用以及酒精引起的细胞改变的临床重要病例中 通过类二十烷酸、视黄酸和其他 P450 依赖性信使发出信号。 本提案旨在探讨酒精诱导的 P450 表达变化及其对 内质网膜中蛋白质-蛋白质相互作用的网络，从而影响整个系统的特性 P450 乐团的成员。我们的长期目标是获得各功能之间相互作用的完整图景 人类细胞色素 P450，特别是酒精诱导型 P450 物种，并描述了它们在 决定药物代谢整体的整体特性及其随饮酒的变化。 该项目的具体目标是：（1）完善我们对酒精引起的成分变化的了解 肝细胞中的细胞色素 P450 群； (2) 确定酒精的主要分子间相互作用 在 HLM 中诱导 P450 物种； (3) 确定酒精诱导的P450的主要功能相互作用 与其他 P450 物种的酶并探索它们对药物和内源底物代谢的影响 由 P450 合奏。实现这些目标将有助于深入描述酒精引起的变化 药物代谢和 P450 依赖性细胞信号传导，并了解它们在有害酒精药物中的作用 饮酒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.

细胞色素 P450 依赖性药物去甲基化反应的高通量测定及其用于重新评估氯胺酮代谢途径的用途。

• 发表时间: 2023-07-27
• 影响因子: 4.2
• 作者: Davydova, Nadezhda Y;Hutner, David A;Gaither, Kari A;Singh, Dilip Kumar;Prasad, Bhagwat;Davydov, Dmitri R
• 通讯作者: Davydov, Dmitri R