Lim Joe Jongpyo, Klaassen Curtis Dean, Cui Julia Yue
Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington; Environmental Health and Microbiome Research Center (EHMBRACE), Seattle, Washington.
Department of Pharmacology, Toxicology, and Therapeutics, School of Medicine, University of Kansas, Kansas City, Kanas.
Drug Metab Dispos. 2025 Feb;53(2):100029. doi: 10.1016/j.dmd.2024.100029. Epub 2024 Dec 12.
The liver contains multiple cell types, including resident cell types and immune cells. The liver is also categorized into 3 zones: periportal (zone 1), midzonal (zone 2), and centrilobular (zone 3). The goal of this study was to characterize the distribution of drug-processing genes (DPGs) in mouse liver using published single-cell and nuclei transcriptomic datasets, which were subjected to zonal deconvolution. Filtering, normalization, clustering, and differential expression analyses were performed using Seurat V5 in R. Hepatocytes were assigned to 3 zones based on known zonal markers and validated with published spatial transcriptomics data. Among the 195 DPGs profiled, most were expressed highest in hepatocytes (61.3%). Interestingly, certain DPGs were expressed most highly in nonparenchymal cells, such as in cholangiocytes (11.2%, eg, carboxylesterase [Ces] 2e, Ces2g), endothelial cells (7.2%, eg, aldo-keto reductase [Akr] 1c19, Akr1e1), Kupffer cells (5.3%, eg, Akr1a1, Akr1b10), stellate cells (5.1%, eg, retinoic acid receptor [Rar] α, Rarβ), myofibroblasts (2.9%, RAR-related orphan receptor [Rar] α), and a few were expressed in immune cell types. In hepatocytes, 72.4% of phase-I enzymes were enriched in zone 3. Phase-II conjugation enzymes such as UDP-glucuronosyltransferases (75%) were enriched in zone 3, whereas sulfotransferases (40%) were enriched in zone 1. Hepatic xenobiotic transporters were enriched in zone 3. The xenobiotic biotransformation-regulating transcription factors were enriched in zone 3 hepatocytes. The enrichment of DPGs in liver cell types, including non-parenchymal cells and zone 1 hepatocytes, may serve as an additional repertoire for xenobiotic biotransformation. SIGNIFICANCE STATEMENT: Our study is among the first to systematically characterize the baseline mRNA enrichment of important drug-processing genes in different cell types and zones in the liver. This finding will aid in further understanding the mechanisms of chemical-induced liver injury with improved resolution and precision.
肝脏包含多种细胞类型，包括驻留细胞类型和免疫细胞。肝脏也被分为三个区域：门周区（1区）、中区（2区）和中央静脉周围区（3区）。本研究的目的是利用已发表的单细胞和细胞核转录组数据集，对小鼠肝脏中药物加工基因（DPG）的分布进行表征，并对这些数据集进行区域反卷积分析。使用R语言中的Seurat V5进行过滤、标准化、聚类和差异表达分析。根据已知的区域标记物将肝细胞分为三个区域，并用已发表的空间转录组学数据进行验证。在分析的195个DPG中，大多数在肝细胞中表达最高（61.3%）。有趣的是，某些DPG在非实质细胞中表达最高，如胆管细胞（11.2%，如羧酸酯酶[Ces]2e、Ces2g）、内皮细胞（7.2%，如醛糖还原酶[Akr]1c19、Akr1e1）、库普弗细胞（5.3%，如Akr1a1、Akr1b10）、星状细胞（5.1%，如视黄酸受体[Rar]α、Rarβ）、肌成纤维细胞（2.9%，RAR相关孤儿受体[Rar]α），还有一些在免疫细胞类型中表达。在肝细胞中，72.4%的I相酶在3区富集。II相结合酶如UDP-葡萄糖醛酸转移酶（75%）在3区富集，而磺基转移酶（40%）在1区富集。肝脏外源性物质转运体在3区富集。外源性物质生物转化调节转录因子在3区肝细胞中富集。DPG在包括非实质细胞和1区肝细胞在内的肝细胞类型中的富集可能是外源性物质生物转化的另一种机制。意义声明：我们的研究是首批系统表征肝脏中不同细胞类型和区域中重要药物加工基因基线mRNA富集情况的研究之一。这一发现将有助于以更高的分辨率和精度进一步了解化学性肝损伤的机制。
