更新于：2024-09-19

SLC22A5

更新于：2024-09-19

基本信息

别名

CDSP、High-affinity sodium-dependent carnitine cotransporter、OCTN2

+ [5]

简介

Sodium-ion dependent, high affinity carnitine transporter. Involved in the active cellular uptake of carnitine. Transports one sodium ion with one molecule of carnitine (PubMed:10454528, PubMed:10525100, PubMed:10966938, PubMed:17509700, PubMed:20722056). Also transports organic cations such as tetraethylammonium (TEA) without the involvement of sodium. Relative uptake activity ratio of carnitine to TEA is 11.3 (PubMed:10454528, PubMed:10525100, PubMed:10966938). In intestinal epithelia, transports the quorum-sensing pentapeptide CSF (competence and sporulation factor) from Bacillus Subtilis wich induces cytoprotective heat shock proteins contributing to intestinal homeostasis (PubMed:18005709). May also contribute to regulate the transport of organic compounds in testis across the blood-testis-barrier (Probable). Retained in the ER, unable to perform carnitine uptake.

关联

项与 SLC22A5 相关的药物

Meldonium hydrate

米屈肼

靶点

BBOX x SLC22A5

作用机制

BBOX拮抗剂 [+1]

在研机构

扬子江药业集团北京海燕药业有限公司 [+2]

原研机构-

在研适应症

酗酒 [+4]

非在研适应症

脑血管疾病

最高研发阶段批准上市

首次获批国家/地区-

首次获批日期1800-01-20

项与 SLC22A5 相关的临床试验

CTIS2023-509804-14-00 / Not yet recruitingIIT

The role of meldonium and individualized physical activities in the treatment of patients with heart failure - MELD-PHYS-2023

开始日期2024-03-27

申办/合作机构-

CTR20140220 / Suspended临床3期

评估标准加米屈肼治疗慢性缺血性心力衰竭患者有效性和安全性的双盲、随机、安慰剂平行对照、多中心临床研究

主要目标：评估标准治疗加米屈肼相比较于标准治疗加安慰剂治疗慢性缺血性心衰病人 (NYHA II- III 级）的疗效次要目标：评估米屈肼治疗慢性缺血性心衰病人的安全性

开始日期2014-07-14

申办/合作机构

Jsc Grindeks

[+1]

CTR20131432 / Active, not recruiting临床1期

米屈肼注射液人体药代动力学试验

本次试验的目的是对米屈肼注射液进行人体药代动力学研究，研究米屈肼注射液在健康受试者中单次和多次给药的药代动力学研究，以了解米屈肼注射液在中国人体内的药代动力学规律，为临床研究给药方案提供依据。

开始日期2013-06-04

申办/合作机构

Jsc Grindeks

[+1]

100 项与 SLC22A5 相关的临床结果

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100 项与 SLC22A5 相关的转化医学

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0 项与 SLC22A5 相关的专利（医药）

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673

项与 SLC22A5 相关的文献（医药）

2024-10-01·Molecular Metabolism

Imatinib therapy of chronic myeloid leukemia significantly reduces carnitine cell intake, resulting in adverse events

Article

OBJECTIVEA prominent, safe and efficient therapy for patients with chronic myeloid leukemia (CML) is inhibiting oncogenic protein BCR::ABL1 in a targeted manner with imatinib, a tyrosine kinase inhibitor. A substantial part of patients treated with imatinib report skeletomuscular adverse events affecting their quality of life. OCTN2 membrane transporter is involved in imatinib transportation into the cells. At the same time, the crucial physiological role of OCTN2 is cellular uptake of carnitine which is an essential co-factor for the mitochondrial β-oxidation pathway. This work investigates the impact of imatinib treatment on carnitine intake and energy metabolism of muscle cells.METHODSHTB-153 (human rhabdomyosarcoma) cell line and KCL-22 (CML cell line) were used to study the impact of imatinib treatment on intracellular levels of carnitine and vice versa. The energy metabolism changes in cells treated by imatinib were quantified and compared to changes in cells exposed to highly specific OCTN2 inhibitor vinorelbine. Mouse models were used to test whether in vitro observations are also achieved in vivo in thigh muscle tissue. The analytes of interest were quantified using a Prominence HPLC system coupled with a tandem mass spectrometer.RESULTSThis work showed that through the carnitine-specific transporter OCTN2, imatinib and carnitine intake competed unequally and intracellular carnitine concentrations were significantly reduced. In contrast, carnitine preincubation did not influence imatinib cell intake or interfere with leukemia cell targeting. Blocking the intracellular supply of carnitine with imatinib significantly reduced the production of most Krebs cycle metabolites and ATP. However, subsequent carnitine supplementation rescued mitochondrial energy production. Due to specific inhibition of OCTN2 activity, the influx of carnitine was blocked and mitochondrial energy metabolism was impaired in muscle cells in vitro and in thigh muscle tissue in a mouse model.CONCLUSIONSThis preclinical experimental study revealed detrimental effect of imatinib on carnitine-mediated energy metabolism of muscle cells providing a possible molecular background of the frequently occurred side effects during imatinib therapy such as fatigue, muscle pain and cramps.

2024-08-20·Journal of the American Heart Association

Systematic Druggable Genome‐Wide Mendelian Randomization Identifies Therapeutic Targets for Functional Outcome After Ischemic Stroke

Article

作者: You, Yun‐Fan ; Dong, Ming‐Hao ; Zhu, Li‐Fang ; Chu, Yun‐Hui ; Yang, Sheng ; Zhang, Lu‐Yang ; Deng, Gang ; Shang, Ke ; Xiao, Jun ; Pang, Xiao‐Wei ; Zhou, Luo‐Qi ; Qin, Chuan ; Wang, Wei ; Tian, Dai‐Shi ; Chen, Lian

BackgroundStroke is a leading cause of death worldwide, with a lack of effective treatments for improving the prognosis. The aim of the present study was to identify novel therapeutic targets for functional outcome after ischemic stroke .Methods and Results Cis‐expression quantitative trait loci data for druggable genes were used as instrumental variables. The primary outcome was the modified Rankin Scale score at 3 months after ischemic stroke, evaluated as a dichotomous variable (3–6 versus 0–2) and also as an ordinal variable. Drug target Mendelian randomization, Steiger filtering analysis, and colocalization analysis were performed. Additionally, phenome‐wide Mendelian randomization analysis was performed to identify the safety of the drug target genes at the genetic level. Among >2600 druggable genes, genetically predicted expression of 16 genes ( ABCC2 , ATRAID , BLK , CD93 , CHST13 , NR1H3 , NRBP1 , PI3 , RIPK4 , SEMG1 , SLC22A4 , SLC22A5 , SLCO3A1 , TEK , TLR4 , and WNT10B ) demonstrated the causal associations with ordinal modified Rankin Scale ( P <1.892×10 −5 ) or poor functional outcome (modified Rankin Scale 3–6 versus 0–2, P <1.893×10 −5 ). Steiger filtering analysis suggested potential directional stability ( P <0.05). Colocalization analysis provided further support for the associations between genetically predicted expression of ABCC2 , NRBP1 , PI3 , and SEMG1 with functional outcome after ischemic stroke. Furthermore, phenome‐wide Mendelian randomization revealed additional beneficial indications and few potential safety concerns of therapeutics targeting ABCC2 , NRBP1 , PI3 , and SEMG1 , but the robustness of these results was limited by low power. ConclusionsThe present study revealed 4 candidate therapeutic targets for improving functional outcome after ischemic stroke, while the underlying mechanisms need further investigation.

2024-08-01·Chemico-Biological Interactions

Downregulation of OATP2B1 by proinflammatory cytokines leads to 5-ASA hyposensitivity in Ulcerative colitis

Article

作者: Wang, Jinhai ; Lin, Nengming ; Pan, Xiaoyi ; Li, Ping ; Zhou, Hui ; Dong, Minlei ; Chen, Binxin ; Jiang, Huidi ; Luo, Jun ; Duan, Yangri ; Jiang, Yiming

5-Aminosalicylic acid (5-ASA) is a first-line agent in both remission and maintenance therapy for ulcerative colitis (UC). However, the mucosal concentration of 5-ASA was significantly lower in patients with severe histological inflammation, which further led to a poor response to 5-ASA treatment. Our study aimed to clarify the mechanism of 5-ASA uptake into colonic epithelial cells and to further explore the reason for the decreased colonic mucosal 5-ASA concentration in UC patients. Our results demonstrated that the colonic 5-ASA concentration was notably reduced in DSS-induced colitis mice and inversely correlated with colonic inflammation. 5-ASA was not a substrate of carnitine/organic cation transporter 1/2 (OCTN1/2) or multidrug resistance protein 1 (MDR1), whereas organic anion transporting polypeptide 2B1 (OATP2B1) and sodium-coupled monocarboxylate transporter 1 (SMCT1) mediated the uptake of 5-ASA, with a greater contribution from OATP2B1 than SMCT1. Inhibitors and siRNAs targeting OATP2B1 significantly reduced 5-ASA absorption in colonic cell lines. Moreover, OATP2B1 expression was dramatically downregulated in colon tissues from UC patients and dextran sodium sulfate (DSS)-induced colitis mice, and was also negatively correlated with colonic inflammation. Mechanistically, mixed proinflammatory cytokines downregulated the expression of OATP2B1 in a time- and concentration-dependent manner through the hepatocyte nuclear factor 4 α (HNF4α) pathway. In conclusion, OATP2B1 was the pivotal transporter involved in colonic 5-ASA uptake, which indicated that inducing OATP2B1 expression may be a strategy to promote 5-ASA uptake and further improve the concentration and anti-inflammatory efficacy of 5-ASA in UC.