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在各种细胞系中,阿曼胺诱导的可变细胞毒性是由OATP1B3的不同表达水平介导的
Mengqiang Gong1, Zhi Li2, Hua Xu2
1School of Agriculture, Yangtze University, Jingzhou, 434025, China; Laboratory of Toxicant Analysis, Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, Beijing, 100850, China.
概括
从Amanita phalloides中致命的中毒通常是致命的,因为致命的毒素称为阿曼尼丁. 这项研究确定了有机离子运输聚1B3 (OATP1B3) 作为阿曼尼丁的关键.
科学领域:
- 毒理学 毒理学 毒理学
- 分子生物学分子生物学
- 细胞生物学 细胞生物学
背景情况:
- 阿曼尼塔类在全球范围内引起致命的中毒,阿曼尼是主要的致命毒素.
- 目前对阿马尼中毒的治疗方法缺乏有效性,并且没有特定的抗药物.
- 亚马尼丁主要影响肝脏,胃和脏等器官,对于这种器官特异性的机制尚不清楚.
研究的目的:
- 调查阿曼尼丁的器官特异性毒性背后的分子机制.
- 确定导致不同人类细胞系对阿马尼暴露的不同敏感性的因素.
主要方法:
- 来自不同器官的8个人类细胞系暴露于不同度的α,β和γ-amanitin (0.3100μM).
- 评估跨细胞系的差异性细胞毒性.
- 研究有机离子载体聚1B3 (OATP1B3) 在阿曼的吸收和毒性的作用.
- 在HepG2细胞中抑制OATP1B3,以评估其对α-amanitin诱导的细胞毒性的影响.
主要成果:
- 在不同的人类细胞系中观察到阿马尼细胞毒性的显著变化.
- 肝脏 (HepG2),胃 (BGC-823) 和 (HEK-293) 细胞系对阿马尼的敏感性最高.
- 不同的细胞毒性与OATP1B3的不同表达水平相关,OATP1B3是一种促进阿马尼进入细胞的载体.
- 在HepG2细胞中OATP1B3的淘汰显著降低了α-amanitin诱导的细胞毒性.
结论:
- OATP1B3的表达水平是阿马尼器官特异性细胞毒性的关键决定因素.
- OATP1B3在调解阿马尼内部化和随后的细胞损伤方面发挥着至关重要的作用.
- 向OATP1B3为管理阿马尼诱导器官衰竭提供了潜在的治疗策略.
相关概念视频
01:27ATP Driven Pumps I: An Overview
ATP-driven pumps, also known as transport ATPases, are integral membrane proteins. They have binding sites for ATP located on the membrane's cytosolic side and the ion-conducting domain in the transmembrane region. These pumps use the free energy released from ATP hydrolysis to move the solutes across cell membranes against an electrochemical gradient.
There are four main types of ATP-driven pumps - P-type, V-type, F-type, and ABC transporter. All these pumps are of varying complexities and are...
There are four main types of ATP-driven pumps - P-type, V-type, F-type, and ABC transporter. All these pumps are of varying complexities and are...
01:31ABC Transporters: Exporter
ATP-binding cassette or ABC transporter is the largest superfamily of integral membrane proteins. The transporters have transmembrane-binding domains (TMDs) and nucleotide-binding domains (NBDs). The TMDs are specific to their substrates, whereas the NBDs are similar to engines that complete ATP hydrolysis to complete the substrate transport. They can be full transporters consisting of two TMDs and NBDs, half transporters with one TMD and NBD, while some encoded with a single TMD or NBD are...
01:30ATP Driven Pumps III: V-type Pumps
V-type pumps are ATP-driven pumps found in the vacuolar membranes of plants, yeast, endosomal and lysosomal membranes of animal cells, plasma membranes of a few specialized eukaryotic cells, and some prokaryotes. They are also known as the V1Vo-ATPase, that couple ATP hydrolysis to transport protons against a concentration gradient.
The peripheral or cytosolic V1 domain with eight subunits is involved in ATP hydrolysis. The integral or transmembrane V0 domain containing at least five subunits...
The peripheral or cytosolic V1 domain with eight subunits is involved in ATP hydrolysis. The integral or transmembrane V0 domain containing at least five subunits...
01:06Carrier-Mediated Transport
Carrier-mediated transport is a pivotal process in drug absorption, particularly for lipid-insoluble drugs, and encompasses facilitated diffusion and active transport. Facilitated diffusion allows drugs to move along their concentration gradient without energy expenditure, while active transport utilizes ATP to drive drug movement against this gradient.
Active transport involves two types of membrane-spanning transporters: uptake and efflux. Uptake transporters are expressed in the small...
Active transport involves two types of membrane-spanning transporters: uptake and efflux. Uptake transporters are expressed in the small...
01:14Active Transport
Active transport is a critical biological process that allows cells to move solutes against an electrochemical gradient. This process requires direct energy input and is characterized by its selectivity, saturability, and susceptibility to competitive inhibition.
Primary active transporters, like Na+, K+ and -ATPase, directly utilize ATP to move ions across the membrane. These transporters play significant roles in various physiological processes. For instance, Na+, K+ and -ATPase maintain...
Primary active transporters, like Na+, K+ and -ATPase, directly utilize ATP to move ions across the membrane. These transporters play significant roles in various physiological processes. For instance, Na+, K+ and -ATPase maintain...
01:16Pharmacogenetics of Drug Transporters: P-Glycoprotein and Solute Carrier Transporters
The pharmacogenetics of drug transporters is increasingly recognized as a critical factor influencing interindividual variability in drug absorption, distribution, and elimination. These membrane-bound proteins regulate drugs' movement across cellular barriers by actively pumping them out (efflux) or facilitating their uptake (influx). Among the major transporter families, ATP-binding cassette (ABC) and solute carrier (SLC) transporters play particularly prominent roles. Genetic polymorphisms...