Barata Isabel S, Rueff José, Kranendonk Michel, Esteves Francisco
Department of Pediatrics, Division of Endocrinology, Diabetology and Metabolism, University Children's Hospital, University of Bern, 3010 Bern, Switzerland.
Translational Hormone Research Program, Department of Biomedical Research, University of Bern, 3010 Bern, Switzerland.
J Xenobiot. 2024 May 1;14(2):575-603. doi: 10.3390/jox14020034.
Progesterone receptor membrane component 1 (PGRMC1) is one of few proteins that have been recently described as direct modulators of the activity of human cytochrome P450 enzymes (CYP)s. These enzymes form a superfamily of membrane-bound hemoproteins that metabolize a wide variety of physiological, dietary, environmental, and pharmacological compounds. Modulation of CYP activity impacts the detoxification of xenobiotics as well as endogenous pathways such as steroid and fatty acid metabolism, thus playing a central role in homeostasis. This review is focused on nine main topics that include the most relevant aspects of past and current PGRMC1 research, focusing on its role in CYP-mediated drug metabolism. Firstly, a general overview of the main aspects of xenobiotic metabolism is presented (I), followed by an overview of the role of the CYP enzymatic complex (IIa), a section on human disorders associated with defects in CYP enzyme complex activity (IIb), and a brief account of cytochrome (cyt )'s effect on CYP activity (IIc). Subsequently, we present a background overview of the history of the molecular characterization of PGRMC1 (III), regarding its structure, expression, and intracellular location (IIIa), and its heme-binding capability and dimerization (IIIb). The next section reflects the different effects PGRMC1 may have on CYP activity (IV), presenting a description of studies on the direct effects on CYP activity (IVa), and a summary of pathways in which PGRMC1's involvement may indirectly affect CYP activity (IVb). The last section of the review is focused on the current challenges of research on the effect of PGRMC1 on CYP activity (V), presenting some future perspectives of research in the field (VI).
孕激素受体膜成分1（PGRMC1）是最近被描述为人类细胞色素P450酶（CYP）活性直接调节剂的少数蛋白质之一。这些酶形成了一个膜结合血红素蛋白超家族，可代谢多种生理、饮食、环境和药理化合物。CYP活性的调节影响外源性物质的解毒以及内源性途径，如类固醇和脂肪酸代谢，因此在体内平衡中起着核心作用。本综述聚焦于九个主要主题，包括PGRMC1过去和当前研究中最相关的方面，重点是其在CYP介导的药物代谢中的作用。首先，介绍了外源性物质代谢主要方面的概述（I），接着是CYP酶复合物作用的概述（IIa），关于与CYP酶复合物活性缺陷相关的人类疾病的章节（IIb），以及细胞色素（cyt）对CYP活性影响的简要说明（IIc）。随后，我们介绍了PGRMC1分子特征研究历史的背景概述（III），涉及其结构、表达和细胞内定位（IIIa），以及其血红素结合能力和二聚化（IIIb）。下一部分反映了PGRMC1可能对CYP活性产生的不同影响（IV），介绍了对CYP活性直接影响的研究描述（IVa），以及PGRMC1参与可能间接影响CYP活性的途径总结（IVb）。综述的最后一部分聚焦于PGRMC1对CYP活性影响研究的当前挑战（V），介绍了该领域研究的一些未来前景（VI）。
