Department of Forensic Medicine, Aarhus University, Aarhus, Denmark (K.W.P., J.H., J.B.H., J.R.J.) and Department of Forensic Medicine, University of Copenhagen, Copenhagen, Denmark (J.B.).
Department of Forensic Medicine, Aarhus University, Aarhus, Denmark (K.W.P., J.H., J.B.H., J.R.J.) and Department of Forensic Medicine, University of Copenhagen, Copenhagen, Denmark (J.B.)
Drug Metab Dispos. 2023 Sep;51(9):1169-1176. doi: 10.1124/dmd.122.001125. Epub 2023 May 31.
In this study, we used human postmortem tissue to investigate hepatic protein expression levels of cytochrome P450 (CYP) 1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 by LC-MS/MS in a population of people suffering from mental disorders ( = 171). We report hepatic protein levels of these six CYP isoforms in 171 individuals in total, and define a focused population dataset of 116 individuals after excluding 55 samples due to low microsomal protein per gram of liver (MPPGL) yield. Postmortem decay was most likely the reason for the low MPPGL yield in the 55 samples. In the focused population, we found women to have significantly higher protein levels of CYP3A4 than men in addition to decreased CYP3A4 protein levels among obese individuals. Furthermore, MPPGL was negatively correlated with body mass index (BMI). An increase in CYP1A2 protein levels was observed among smokers, and increased CYP2E1 protein levels were observed among individuals with a history of alcohol abuse. Finally, individuals who received phenobarbital (CYP3A4 inducer) had significantly higher CYP3A4 levels. In conclusion, lifestyle-related factors prevalent among people suffering from mental disorders are associated with altered CYP protein levels, which may alter drug metabolism and affect the efficacy of commonly prescribed drugs. Furthermore, this investigation demonstrates that postmortem hepatic tissue can be used to study how lifestyle and effectors affect hepatic CYP-levels in a large cohort of patients. SIGNIFICANCE STATEMENT: Using a large number of postmortem hepatic tissue specimens (=116) originating from the autopsy of individuals diagnosed with mental disorders, we were able to show that hepatic CYP-levels were affected by alcohol, smoking, BMI, and sex and that MPPGL was affected by BMI. These lifestyle-related changes may alter drug metabolism and affect the efficacy of commonly prescribed drugs. It is a novel approach to use a large postmortem cohort to investigate how lifestyle and effectors affect hepatic CYP-levels.
在这项研究中，我们使用人类死后组织，通过 LC-MS/MS 法调查了患有精神障碍的人群（n=171）中细胞色素 P450（CYP）1A2、CYP2C9、CYP2C19、CYP2D6、CYP2E1 和 CYP3A4 的肝蛋白表达水平。我们总共报告了 171 个人的这六种 CYP 同工酶的肝蛋白水平，并在排除 55 个由于每克肝微粒体蛋白（MPPGL）产量低而导致的样本后，定义了一个聚焦人群数据集（n=116）。55 个样本中 MPPGL 产量低的最可能原因是死后降解。在聚焦人群中，我们发现女性的 CYP3A4 蛋白水平明显高于男性，肥胖个体的 CYP3A4 蛋白水平也降低。此外，MPPGL 与体重指数（BMI）呈负相关。吸烟者 CYP1A2 蛋白水平升高，有酒精滥用史的个体 CYP2E1 蛋白水平升高。最后，接受苯巴比妥（CYP3A4 诱导剂）治疗的个体 CYP3A4 水平显著升高。总之，精神障碍患者中常见的与生活方式相关的因素与 CYP 蛋白水平的改变有关，这可能改变药物代谢，影响常用药物的疗效。此外，本研究表明，死后肝组织可用于研究生活方式和效应物如何影响大量患者的肝 CYP 水平。
使用大量源自被诊断为精神障碍的个体尸检的死后肝组织标本（n=116），我们能够表明肝 CYP 水平受酒精、吸烟、BMI 和性别影响，而 MPPGL 受 BMI 影响。这些与生活方式相关的变化可能改变药物代谢，影响常用药物的疗效。使用大型死后队列研究生活方式和效应物如何影响肝 CYP 水平是一种新颖的方法。
