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

酒精消费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。其作用机制与酒精对药物的影响密切相关。 代谢系统，特别是对细胞色素P450系谱。细胞色素的功能多样性 P450系统是通过十几种不同底物的P450物种的存在而实现的 专一性。众所周知，这个组合的组成在很大程度上受到饮酒的影响。它是 通常假定该集合的积分性质表示这些性质的简单集合 组成P450酶。尽管这一前提仍然是理性分析 药物新陈代谢的途径，其有效性基本上受到了损害。全系统的证据主体 P450合奏的性能集成持续增长。当前项目的提示者为 认识种间串扰的深远生理意义和药理意义 在P450整体及其与酒精对药物代谢和P450的影响的彻底关联中- 依赖的细胞信号。 我们的中心假设是酒精引起的细胞色素组成的变化 P450池并不局限于酒精诱导的酶活性的直接后果。他们也 涉及各种P450的多种外源和内源底物的代谢变化 由于它们与酒精诱导的P450物种相互作用所致。这些间接影响是深层次的。 酒精与药物相互作用和酒精引起的细胞改变的临床重要病例 通过二十碳二烯酸、维甲酸和其他依赖于P450的信使传递信号。 本研究旨在探讨酒精诱导的P450表达的变化及其对大鼠脑内P450表达的影响。 ER膜中蛋白质-蛋白质相互作用的网络，从而对系统范围的性质的影响 P450乐团的成员。我们的长期目标是全面了解 人细胞色素P450，特别是酒精诱导的P450物种，并表征它们在 规定了药物代谢总体的整体性质以及它们因饮酒而发生的变化。 该项目的具体目标是：(1)完善我们对酒精引起的酒精成分变化的知识 细胞色素P450在肝细胞中的表达；(2)确定乙醇-乙醇的主要分子间相互作用。 (3)确定酒精诱导的P450的主要功能相互作用。 酶与其他P450物种的相互作用及其对药物和内源底物代谢的影响 由P450合奏。实现这些目标将允许对酒精引起的变化进行深入的表征 药物代谢和P450依赖的细胞信号转导及其在有害酒精药物中的作用 酒精消费的相互作用和其他不利影响。

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.