药学学报

Disease	Blood-brain barrier	Drug transporter	Drug metabolizing enzyme	Ref.
Multiple sclerosis	Tight junctions related protein expression changed	P-gp, ↓ BCRP, ↓ MRP1, ↓	CYP2B6 CYP2C9 CYP27B1 CYP2R1	[13-16]
Traumatic brain injury	Claudin-5, ↓ Caveolin-1, ↑	P-gp, ↓ Mfsd2a (possible), ↓	CYP1B1 CYP1A21 CYP2B1 CYP2D1 CYP3A2	[17-21]
Parkinson's disease	ZO-1, ↓ Occludin, ↓	P-gp, ↓ MRP2, ↑	CYP2D6 CYP2C19 CYP2B6 CYP1A2	[22-27]
Alzheimer's disease	Tight junctions abnormal	P-gp, ↓ MRP1, ↓ BCRP, ↑ MRP4, ↑ OATP2B1, ↓ Mfsd2a (possible), ↓	CYP3A CYP2D6	[17, 28-33]
Epilepsy	Tight junctions related protein expression changed	P-gp, ↑ BCRP, ↑ MRP1, ↑ MRP2, ↑	CYP3A4 CYP3A5 CYP2B6 CYP2D6	[16, 17, 34-37]
Stroke	Claudin-5, ↓ ZO-1, ↓ Caveolin-1, ↑	P-gp, ↑ MRP4, ↑ BCRP, ↑ MRP1, ↓ OATP1A2, ↑ Mfsd2a (possible), ↓	CYP2C19	[34, 38-43]
Brain tumor	ZO-1, ↓ Claudin-5, ↓	P-gp, ↑ BCRP, ↑ Mfsd2a (possible), ↓	CYP46A1 CYP1B1 CYP3A4	[17, 44-47]

Disease	Blood-brain barrier	Drug transporter	Drug metabolizing enzyme	Ref.
Multiple sclerosis	Tight junctions related protein expression changed	P-gp, ↓ BCRP, ↓ MRP1, ↓	CYP2B6 CYP2C9 CYP27B1 CYP2R1	[13-16]
Traumatic brain injury	Claudin-5, ↓ Caveolin-1, ↑	P-gp, ↓ Mfsd2a (possible), ↓	CYP1B1 CYP1A21 CYP2B1 CYP2D1 CYP3A2	[17-21]
Parkinson's disease	ZO-1, ↓ Occludin, ↓	P-gp, ↓ MRP2, ↑	CYP2D6 CYP2C19 CYP2B6 CYP1A2	[22-27]
Alzheimer's disease	Tight junctions abnormal	P-gp, ↓ MRP1, ↓ BCRP, ↑ MRP4, ↑ OATP2B1, ↓ Mfsd2a (possible), ↓	CYP3A CYP2D6	[17, 28-33]
Epilepsy	Tight junctions related protein expression changed	P-gp, ↑ BCRP, ↑ MRP1, ↑ MRP2, ↑	CYP3A4 CYP3A5 CYP2B6 CYP2D6	[16, 17, 34-37]
Stroke	Claudin-5, ↓ ZO-1, ↓ Caveolin-1, ↑	P-gp, ↑ MRP4, ↑ BCRP, ↑ MRP1, ↓ OATP1A2, ↑ Mfsd2a (possible), ↓	CYP2C19	[34, 38-43]
Brain tumor	ZO-1, ↓ Claudin-5, ↓	P-gp, ↑ BCRP, ↑ Mfsd2a (possible), ↓	CYP46A1 CYP1B1 CYP3A4	[17, 44-47]

Blood-brain barrier	Drug transporter	Drug metabolizing enzyme	Ref.
ZO-1, ↓ Claudin-5, ↓ Occludin, ↓ Caveolin-1, － Increased permeability	Mfsd2a (possible), ↓ P-gp, ↑ BCRP, ↓ MRP-1, ↑ OATP1A4, ↑ OAT, － OCT, － GLUT1, ↑	CYP1A1, ↓ CYP1B1, ↓ CYP2C11, ↑ CYP46A1, ↑ UGT1A1, － GST, ↑	[49-51] [66, 69-71, 73, 74] [79-81, 84, 85]

Blood-brain barrier	Drug transporter	Drug metabolizing enzyme	Ref.
ZO-1, ↓ Claudin-5, ↓ Occludin, ↓ Caveolin-1, － Increased permeability	Mfsd2a (possible), ↓ P-gp, ↑ BCRP, ↓ MRP-1, ↑ OATP1A4, ↑ OAT, － OCT, － GLUT1, ↑	CYP1A1, ↓ CYP1B1, ↓ CYP2C11, ↑ CYP46A1, ↑ UGT1A1, － GST, ↑	[49-51] [66, 69-71, 73, 74] [79-81, 84, 85]

高原低氧对药物跨血脑屏障转运的调节作用及机制

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刘贵琴 ¹ , 白雪 ¹ , 杨建鑫 ¹ , 段雅彬 ² , 朱俊博 ¹ , 田露 ³ , 李向阳 ¹^,⁴^,^*

药学学报 | 综述 2023,58(3): 659-671

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药学学报 | 综述 2023, 58(3): 659-671

高原低氧对药物跨血脑屏障转运的调节作用及机制

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刘贵琴¹, 白雪¹, 杨建鑫¹, 段雅彬², 朱俊博¹, 田露³, 李向阳¹^,⁴^,^*

作者信息

1.青海大学高原医学研究中心, 青海西宁 810001

2.青海大学附属医院, 青海西宁 810001

3.青海大学医学院, 青海西宁 810001

4.青海大学三江源生态与高原农牧业国家重点实验室, 青海西宁 810016

通讯作者:

*李向阳, Tel: 86-971-5362082, Fax: 86-971-5362383, E-mail: qhmclxy@163.com

The modulation and mechanisms of high-altitude hypoxia in drug transport across the blood-brain barrier

Gui-qin LIU¹, Xue BAI¹, Jian-xin YANG¹, Ya-bin DUAN², Jun-bo ZHU¹, Lu TIAN³, Xiang-yang LI¹^,⁴^,^*

Affiliations

1. Research Center for High Altitude Medicine, Qinghai University, Xining 810001, China

2. Affiliated Hospital of Qinghai University, Xining 810001, China

3. Medical College of Qinghai University, Xining 810001, China

4. State Key Laboratory of Plateau Ecology and Agriculture, Qinghai University, Xining 810016, China

出版时间: 2023-03-12 doi: 10.16438/j.0513-4870.2022-1095

文章导航

摘要

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高原低氧环境下机体中枢神经系统功能发生显著改变, 这些变化引发中枢神经系统疾病, 影响药物体内代谢过程。血脑屏障是维持中枢神经系统稳定的必要条件, 在药物代谢调节中发挥关键作用, 屏障结构和功能变化影响药物脑部转运。高原低氧环境下血脑屏障结构和功能及药物跨血脑屏障转运变化, 是受脑微血管内皮细胞、星形胶质细胞和周细胞等细胞调节, 或是受药物转运体和药物代谢酶等药物代谢因素调节。本文通过综述高原低氧环境对血脑屏障结构和功能的影响及血脑屏障变化对药物代谢的影响, 探讨高原低氧环境中血脑屏障与转录因子、炎症因子和核受体等相关通路对药物转运的调节作用及潜在机制。

关键词

血脑屏障 / 高原低氧 / 药物转运体 / 药物代谢酶 / 药物转运

Abstract

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The function of the central nervous system was significantly altered under high-altitude hypoxia, and these changes lead to central nervous system disease and affected the metabolism of drugs in vivo. The blood-brain barrier is essential for maintaining central nervous system stability and plays a key role in the regulation of drug metabolism, and barrier structure and dysfunction affect drug transport to the brain. Changes in the structure and function of the blood-brain barrier and the transport of drugs across the blood-brain barrier under high-altitude hypoxia are regulated by changes in brain microvascular endothelial cells, astrocytes and pericytes, and are regulated by drug metabolism factors such as drug transporters and drug metabolizing enzymes. This article reviews the effects of high-altitude hypoxia on the structure and function of the blood-brain barrier and the effects of changes in the blood-brain barrier on drug metabolism. We investigate the regulatory effects and underlying mechanisms of the blood-brain barrier and related pathways such as transcription factors, inflammatory factors and nuclear receptors on drug transport under high-altitude hypoxia.

Key words

blood-brain barrier / high-altitude hypoxia / drug transporter / drug metabolizing enzyme / drug transport

引用本文

刘贵琴, 白雪, 杨建鑫, 段雅彬, 朱俊博, 田露, 李向阳. 高原低氧对药物跨血脑屏障转运的调节作用及机制. 药学学报, 2023 , 58 (3) : 659 -671 . DOI: 10.16438/j.0513-4870.2022-1095

Gui-qin LIU, Xue BAI, Jian-xin YANG, Ya-bin DUAN, Jun-bo ZHU, Lu TIAN, Xiang-yang LI. The modulation and mechanisms of high-altitude hypoxia in drug transport across the blood-brain barrier[J]. Acta Pharmaceutica Sinica, 2023 , 58 (3) : 659 -671 . DOI: 10.16438/j.0513-4870.2022-1095

正文

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血脑屏障是脑内毛细血管壁与神经胶质细胞形成的选择性运输界面, 严格控制中枢神经系统脑组织和血液间离子、分子和细胞运动, 使脑组织免受细菌、病毒等致病微生物侵害, 维持大脑微环境稳定^[1]。高原环境对机体的影响涉及大气物理、生态环境、地球化学等因素, 其中低压、低氧、强辐射和寒冷干燥为影响人类生命活动的主要因素, 低氧为核心因素, 是人类的面临的最大挑战。机体进入高原环境后中枢神经系统受到不同程度损伤, 进而导致血脑屏障结构和功能障碍, 屏障损伤与脑水肿、脑卒中、阿尔茨海默病和外伤性脑损伤等中枢神经系统疾病密切相关, 并参与疾病的发生、发展和转归, 影响药物脑跨血脑屏障转运及治疗和预后^{[2, 3]}。本文综述了高原低氧对血脑屏障结构和功能的影响及血脑屏障介导的高原低氧对药物代谢的调节机制, 探究高原低氧环境调节中枢神经系统药物转运的靶点, 为提高中枢神经系统药物发挥疗效和促进高原地区中枢神经系统临床合理用药提供新的理论依据。

1 血脑屏障

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血脑屏障由单层无孔的脑微血管内皮细胞、周细胞、星形胶质细胞、小胶质细胞、基底膜和神经元组成^[4], 其中脑微血管内皮细胞具有物理、运输和代谢屏障的特性, 这种特性严格控制血液和脑组织间的物质传递^[5-7], 如图 1。血脑屏障通过被动扩散和主动转运等机制将不同分子量的物质传递至中枢神经系统^[8]。被动扩散是小分子物质进入脑组织的主要方式, 主动转运主要包括主动外排和载体介导的转运^[9], 主动外排促进中枢神经系统药物外排, 血脑屏障中的外排型药物转运体, 将外源性物质和内源性物质通过内皮细胞腔侧主动泵入细胞血液循环, 使毒性代谢物和异源物质排出, 维持大脑生理功能正常^[10]。载体介导的转运促进各种分子的跨细胞运动, 血脑屏障中的溶质转运蛋白是一种独立的能量系统, 帮助药物或内源性物质进入脑组织, 维持大脑营养平衡^[11], 如图 2。然而, 多发性硬化症、帕金森病、阿尔茨海默病、癫痫、脑卒中、脑肿瘤等疾病和低压、低氧、强辐射等环境因素影响中枢神经系统药物转运^[12], 这与血脑屏障结构和功能障碍、药物转运体表达变化及治疗药物受不同药物代谢酶催化密不可分。不同疾病对血脑屏障、药物转运体和药物代谢酶的影响见表 1^[13-47], 但高原低氧等环境因素对血脑屏障和药物转运的影响仍需进一步探索。

2 高原低氧环境对血脑屏障的影响

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高原低氧环境是血脑屏障病理生理变化的初始触发因素, 低氧环境引发水和离子分布改变、炎症因子表达变化、外周免疫细胞向脑组织浸润等反应, 促进脑微血管内皮细胞增殖, 星形胶质细胞和周细胞激活, 影响血脑屏障通透性^{[48, 49]}。因此, 本部分将分析高原低氧环境对血脑屏障脑微血管内皮细胞、星形胶质细胞和周细胞的影响和分子机制变化。

2.1 高原低氧对脑微血管内皮细胞的影响

脑微血管内皮细胞紧临血液, 最先感知血氧分压变化。Fischer等^[50]模拟低氧环境发现低氧降低闭锁连接蛋白-1 (zonula occludens-1, ZO-1) 的表达水平, 增加血脑屏障通透性。Zhang等^[51]研究表明低氧引发内皮细胞和其他损伤细胞内Ca²⁺内流, ATP含量降低, NO释放增多, 使氧化磷酸化、糖酵解和三羧酸循环功能紊乱, 导致紧密连接相关蛋白重排, 血脑屏障通透性增加。Berndt等^[49]发现低氧环境中血脑屏障通透性增加与脑微血管内皮细胞中闭合蛋白-5 (claudin-5) 和咬合蛋白(occludin) 表达下调有关。Park等^[52]研究显示低氧通过调节紧密连接相关蛋白及外排转运体、营养素等受体磷酸化和蛋白质再分配, 改变血脑屏障通透性。以上研究结果主要通过模拟低氧环境发现紧密连接相关蛋白重排或表达水平变化影响脑微血管内皮细胞, 增加血脑屏障通透性, 而高原实地环境对脑微血管内皮细胞的影响及其调控机制还需要进一步实验验证。

2.2 高原低氧对星形胶质细胞的影响

星形胶质细胞与脑微血管内皮细胞共同作用调节血脑屏障。研究显示高原低氧环境中星形胶质细胞分泌白介素-1β (interleukin-1β, IL-1β)、肿瘤坏死因子-α (tumor necrosis factor-α, TNF-α)、血管内皮生长因子(vascular endothelial growth factor, VEGF) 和单核细胞趋化蛋白-1 (monocyte chemotactic protein-1, MCP-1) 等炎症因子促进白细胞在血脑屏障中渗透, 使紧密连接相关蛋白连接紊乱, 屏障通透性增加^[53]。Lu等^[54]研究表明低氧时星形胶质细胞中基质金属蛋白酶-2, 9, 13 (matrix metalloproteinase, MMP-2, 9, 13) 活性增加, 而MMPs会引起紧密连接相关蛋白重组并减弱屏障功能。Mojsilovic-Petrovic等^{[55, 56]}发现低氧环境中星形胶质细胞以氧依赖性方式产生MCP-1, MCP-1由Rho信号介导的紧密连接重排增加脑微血管内皮细胞通透性。此外, 低氧环境下星形胶质细胞也可维持血脑屏障的完整性, 细胞感受氧供减少后启动代偿性低氧保护机制, 通过增加无氧糖酵解、降低自身氧耗和释放促进血管新生因子等途径, 保护血脑屏障结构和功能稳定^[57]。

2.3 高原低氧对周细胞的影响

周细胞是维持和促进血脑屏障通透性修复的关键。研究表明, 适度低氧使周细胞分泌VEGF、血管生成素(angiopoietin, Ang)、转化生长因子-β (transforming growth factor-β, TGF-β)、促红细胞生成素(erythropoietin, EPO)、胶质细胞源性神经营养因子(glial cell derived neurotrophic factor, GDNF) 和神经营养因子(neurotrophin, NT) 等细胞因子维持血脑屏障通透性, 其中分泌最多的是VEGF和Ang^{[58, 59]}。Nomura等^[60]发现脑缺氧期间周细胞表达血管内皮细胞生长因子受体-1 (vascular endothelial growth factor receptor 1, VEGFR-1), 其在空间上限制VEGF的信号传导, 进而维持血脑屏障结构和功能正常。Ribatti等^[61]表明周细胞分泌的Ang-1通过磷脂酰肌醇3激酶-丝氨酸-苏氨酸激酶信号途径促进血管平滑肌细胞成活, 维持血管完整性、减少血管外渗。高原低氧环境中Ang-1分泌量增加^[62], 但血脑屏障中Ang-1如何变化还未见报道, 提示这可能是高原低氧环境下周细胞保护屏障通透性的另一种机制。

如前所述, 高原低氧环境使血脑屏障结构和功能发生一定变化, 如图 3, 但它们对低氧所致屏障变化对药物代谢的影响, 尤其是屏障功能障碍与药物转运间的联系常常被忽视。作者将结合现有文献分析探讨高原低氧环境中血脑屏障变化对药物代谢的影响及药物跨血脑屏障转运的调节作用和分子机制。

3 高原低氧环境中血脑屏障变化对药物代谢的影响和药物转运的调控机制

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3.1 高原低氧环境中血脑屏障变化对药物代谢的影响

3.1.1 高原低氧环境中血脑屏障变化对药物转运体的影响

药物转运体参与药物吸收和跨屏障分布过程, 介导不同组织对药物及代谢产物的排泄^[63]。主要协同转运蛋白超家族是最大和最多样化的膜转运蛋白, 主要促进调解超家族蛋白2A (major facilitator superfamily domain-containing protein 2a, Mfsd2a) 是其成员之一, 主要功能为维持血脑屏障完整性、抑制中枢神经系统内皮细胞转运和减轻血脑屏障损伤^[64]。Han等^[65]提出Mfsd2a通过控制血脑屏障内皮细胞的脂质成分抑制小窝介导的胞吞作用调节血脑屏障通透性, 从而转运大分子药物。Shang等^[66]发现低氧诱导因子-1α (hypoxia inducible factor-1α, HIF-1α) 和血红素加氧酶-1 (heme oxygenase 1, HO-1) 表达增加使Mfsd2a表达降低, 血脑屏障通透性增加, 但高原低氧环境下血脑屏障结构与功能变化对Mfsd2a及药物跨血脑屏障转运的影响还尚未可知。

ATP结合(ATP-binding cassette, ABC) 转运蛋白和可溶性载体(solute carrier, SLC) 转运蛋白共同参与药物跨血脑屏障转运^[67]。血脑屏障中的ABC转运体为P-糖蛋白(P-glycoprotein, P-gp)、乳腺癌耐药蛋白(breast cancer resistance protein, BCRP) 和多药耐药相关蛋白(multidrug resistance-associated protein, MRP) 等, 它们构成血脑屏障的主要转运系统, 一方面限制大多数药物通过血脑屏障, 导致中枢神经系统疾病治疗效果不佳; 另一方面介导药物在脑中的清除和分布, 维持中枢神经系统内稳态^[68]。Ozgür等^[69]探讨低氧对血脑屏障和药物转运体的影响, 发现低氧引起血脑屏障通透性增加和P-gp表达上调, 且P-gp底物地高辛双向运输研究表明地高辛在血脑屏障中的流出率较高, 提示低氧环境中P-gp表达上调减少药物转运, 影响中枢神经系统药物疗效。Zolotoff等^[70]构建体外血脑屏障模型发现慢性间歇低氧6 h引发血脑屏障结构和功能障碍, P-gp表达上调, BCRP表达下调, 进而影响药物转运。Chatard等^[71]研究发现, 低氧应激增加血脑屏障通透性, 但通过上调P-gp和MRP-1表达建立防御机制, 减少血脑屏障损伤和药物转运障碍。SLC转运蛋白主要包括有机阴离子转运多肽(organic anion-transporting polypeptide, OATP)、有机阴离子转运蛋白(organic anion transporters, OAT)、有机阳离子转运蛋白(organic cation transporter, OCT) 和葡萄糖转运蛋白1 (glucose transporter 1, GLUT1) 等, 它们介导多种药物转运^[72]。Thompson等^[73]研究低氧/复氧条件下血脑屏障他汀类药物OATP1A4的调节和功能表达, 发现低氧/复氧(6% O₂, 60 min, 21% O₂, 10 min) 后脑微血管内皮细胞OATP1A4表达上调, 且OATP抑制剂降低了他汀类药物的脑摄取, 表明OATP1A4参与了大脑药物转运。研究表明, 脑缺氧导致大脑能量代谢和葡萄糖利用发生变化, 血脑屏障中GLUT1表达增加, 促进GLUT1介导葡萄糖跨血脑屏障进入神经胶质细胞和神经元, 推测高原低氧环境中葡萄糖包裹的纳米药物载体具有将药物转运到中枢神经系统的潜力^[74]。另外, 本课题组研究发现, 高原低氧环境下药物转运体功能发生变化, P-gp、MRP2、OATP2B1、BCRP底物药物的吸收受到影响, 罗丹明123、长春新碱、格列本脲的吸收均加快, 哌唑嗪的吸收减慢^[75]。

以上研究表明, 高原低氧环境导致的血脑屏障障碍使不同药物转运体的表达发生变化, 影响药物分布和中枢神经系统疾病治疗, 见表 2^{[49-51, 66, 69-71, 73, 74]}。不同药物转运体根据其功能和位置, 可保护中枢神经系统免受外源性毒素的干扰, 促进药物跨血脑屏障转运, 或限制药物进入血脑屏障成为中枢神经系统治疗的障碍。药物转运体的特殊功能提示血脑屏障透过率低的中枢神经系统药物, 可通过调控药物转运体的功能和修饰药物结构等技术, 增加药物与转运体的亲和力促进药物透过屏障。药物转运体在中枢神经系统药物转运中起关键作用, 探明高原低氧环境下血脑屏障变化对药物转运体的影响, 对促进药物跨血脑屏障转运具有重要意义。

3.1.2 高原低氧环境中血脑屏障变化对药物代谢酶的影响

药物代谢酶负责催化药物等外源性物质的代谢, 主要分为Ⅰ相和Ⅱ相药物代谢酶^[76], 临床上近90%的药物相互作用是由Ⅰ相药物代谢酶细胞色素P450 (cytochrome P450, CYP450) 变化引起的。近年来, 脑组织中发现了多种CYP450, 包括CYP1、CYP2、CYP3家族和CYP46A1等近24个CYP450, 其中CYP1A1、CYP1A2、CYP1B1、CYP2B6、CYP2D6和CYP3A4表达较为丰富, 这些CYP450的表达、功能和调节在血脑屏障药物代谢中的作用越来越受到重视^{[77, 78]}。高原低氧环境中血脑屏障结构和功能变化后CYP450的表达也发生一定变化, Lu等^[79]研究显示, 新生小鼠大脑缺氧后血脑屏障通透性增加, 导致负责形成24S羟基胆固醇的CYP46A1表达上调, 从而促进24S羟基胆固醇排出中枢神经系统。Liu等^[80]研究发现, 低氧3 h后大鼠星形胶质细胞出现凋亡现象, 且CYP2C11表达显著增加。Jacob等^[81]在低氧环境干扰人脑微血管内皮细胞芳香烃受体通路研究中发现低氧增加内皮细胞通透性, 下调芳香烃受体靶基因CYP1A1和CYP1B1表达。血脑屏障的Ⅱ相药物代谢酶主要有尿苷5′-二磷酸葡萄糖醛酸转移酶(UDP-glucuronosyl transferase, UGT) 和谷胱甘肽S-转移酶(glutathione S-transferase, GST)^{[82, 83]}。研究报道, UGT1A催化多种药物、神经递质和神经甾体在大鼠不同脑区域的葡萄糖醛酸化, 影响药物在血脑屏障的药理作用^[84]。Xiong等^[85]发现低温低氧环境导致大鼠血脑屏障中GST和谷胱甘肽过氧化物酶表达显著升高, 影响中枢神经系统药物等内源性物质转运。以上结果显示, 高原低氧环境中血脑屏障通透性增加影响药物代谢酶, 使药物代谢和中枢神经系统药物转运发生变化, 见表 2^{[79-81, 84, 85]}。

本课题组通过实地研究表明, 大鼠急进氧分压为15.1 kPa的2 800 m低氧环境3天后CYP1A2的蛋白和mRNA表达均显著降低60.4%和51.1%, 慢性饲养30天后显著降低62.0%和32.9%, 急进氧分压为12.4 kPa的4 300 m低氧环境3天后CYP1A2的蛋白和mRNA表达均显著降低65.8%和37.2%, 慢性饲养30天后显著降低64.8%和30.7%。在4 300 m低氧环境慢性饲养30天后CYP3A1的蛋白和mRNA表达分别降低27.5%和33.7%, CYP2E1分别降低33.9%和52.0%, CYP2D1均显著升高23.5%和34.7%, 但急进4 300 m低氧环对CYP3A1、CYP2E1和CYP2D1的蛋白和mRNA表达无显著影响^{[86, 87]}。以上研究表明, 高原低氧环境对药物代谢酶的活性和表达的影响是双向的, 提示高原低氧环境可促进或降低咪达唑仑、对乙酰氨基酚和右美沙芬等中枢神经系统药物的体内代谢。此外, 本课题组前期研究表明高原低氧环境下对乙酰氨基酚的药物代谢动力学参数发生显著变化, 主要表现为急性和慢性低氧组半衰期(t_1/2) 均显著延长21.7%和40.9%, 血药浓度曲线下面积(AUC) 均显著增加91.9%和133.9%, 清除率(CL) 均显著降低48.1%和56.9%^[88]。截至目前, 尚有研究表明苯巴比妥^[89]、苯妥英钠^[90]、哌替啶^[91]、地西泮^[92]、丁螺环酮^[93]等中枢神经系统药物在高原低氧环境中的体内代谢减慢, 但血脑屏障变化对药物代谢和药物转运的影响仍需进一步实验验证。

3.2 高原低氧环境中血脑屏障变化对药物转运的调控机制

前期研究认为, 高原低氧环境中外周循环中性粒细胞以快速、大流量方式渗透中枢神经系统, 主要堆积在脑微血管内皮细胞内, 局部释放蛋白水解酶、活性氧类等, 使血脑屏障中紧密连接蛋白ZO-1、claudin-5、occludin等重新分布, 引起血脑屏障结构和功能改变, 但高原低氧环境导致血脑屏障生理病理变化和药物代谢变化的内在调节机制有待进一步研究。综合文献报道, 作者主要从转录因子、炎症因子、核受体、微小RNA (microRNA, miRNA) 和肠道菌群与药物转运体和药物代谢酶间的联系探讨相关机制。

3.2.1 转录因子

转录因子参与高原低氧环境所致的血脑屏障损伤, 其中HIF-1α对血脑屏障及药物转运体和药物代谢酶具有重要调控作用。Engelhardt等^[94]发现HIF-1α稳定表达刺激大鼠脑微血管内皮细胞中总蛋白激酶C, 使总蛋白激酶C亚型从细胞质向紧密连接转移, 引起ZO-1、claudin-5、occludin重排及磷酸化, 增加血脑屏障通透性。研究显示, HIF-1α的靶基因VEGF促进ZO-1和occludin的酪氨酸磷酸化, 导致紧密连接失调和血脑屏障通透性增加^[95]。以上研究表明, HIF-1α通路激活诱导紧密连接相关蛋白和VEGF磷酸化, 引起血脑屏障功能障碍。同时, HIF-1α可与低氧反应元件结合, 调控血脑屏障P-gp、BCRP、MPR1和CYP2C11、CYP4A的表达, 影响药物代谢^{[80, 96, 97]}。由此, 推测HIF-1α等转录因子的表达及分子机制变化可能成为调节药物跨血脑屏障转运影响药物代谢的潜在靶点。

3.2.2 炎症因子

血脑屏障是炎症因子的调节界面, 可选择性转运炎症因子, 低氧诱导血脑屏障表达TNF-α、IL-1β、白介素-6 (interleukin-6, IL-6)、TGF-β和成纤维细胞生长因子(basic fibroblast growth factor, bFGF) 等炎症因子^{[98, 99]}。Witt等^[100]报道低氧环境中血脑屏障TNF-α、IL-1β和IL-6表达变化使白细胞外渗至脑实质, 导致紧密连接失调, 血脑屏障通透性增加。此外, 低氧环境中TNF-α、IL-6和IL-1β参与调节肝脏CYP1A2、CYP2C19、CYP2D6和CYP2E1表达^[68], 而血脑屏障中也存在大量药物代谢酶, 表明炎症因子也可能参与调节血脑屏障药物代谢酶的表达。Han等^[65]发现Mfsd2a基因敲除小鼠具有较高的血脑屏障转运率, 且TGF-β和bFGF表达量发生变化, 表示血脑屏障中Mfsd2a表达受TGF-β和bFGF信号通路的协同调控。也有研究表明, 低氧使TGF-β和bFGF表达升高^[99], 但是否会通过TGF-β和bFGF表达升高导致Mfsd2a水平失调, 增加胞吞作用, 改变血脑屏障通透性, 影响药物转运还需进一步研究和验证。

3.2.3 核受体

核受体是调控药物代谢酶和药物转运体的重要调节因子, 包括孕烷X受体(pregnane X receptor, PXR) 和组成型雄烷受体(constitutive androstane receptor, CAR) 等。血脑屏障中PXR和CAR被许多内源性和外源性物质激活, 调节下游药物代谢酶的表达与活性, 如CYP1A1、CYP2B6、CYP2D6、CYP3A4和CYP2E1等^[101]。低氧显著降低PXR和CAR的表达, 研究发现低氧增加血脑屏障通透性引发的信号级联反应通过磷酸化和核因子κB (nuclear factor-kappa B, NF-κB) 激活调节血脑屏障PXR和CAR的表达, 而NF-κB直接或间接调节药物代谢酶表达^[102]。同样, 血脑屏障中PXR和CAR也参与P-gp和BCRP等药物转运体的表达调控, 影响脑中药物代谢^[103]。以上研究表明, 低氧环境可能通过增加血脑屏障通透性和激活NF-κB信号通路抑制或促进核受体的表达, 并与药物代谢酶和药物转运体相互作用, 调节药物跨血脑屏障转运。

3.2.4 miRNA

miRNA参与脑内药物的生物转化, 脑微血管内皮细胞中有166种miRNA, 其中miR-34a、miR-99b、miR-20b和miR-337-3p在内皮细胞中表达量较高, 且在血脑屏障的功能调节中发挥重要调控作用^[104]。Bukeirat等^[105]发现miR-34a表达触发血脑屏障功能障碍, 减少线粒体氧化磷酸化, 降低细胞色素C水平, 导致内源性物质跨膜转运变化, 表明miR-34a通过调控血脑屏障通透性和线粒体功能, 影响中枢神经系统药物转运。Wang等^[106]研究表明脑缺血缺氧使血脑屏障miR-337-3p水平升高, 大鼠尾静脉给予化学修饰的miR-337抑制剂后, 其可跨血脑屏障运输, 引发miR-337-3p下调并减少缺血缺氧引起的脑损伤和神经功能障碍。本课题组研究显示Caco-2细胞中miRNA-873-5p介导低氧环境对MDR1和PXR表达, 发挥调节药物代谢作用, 表明低氧环境中miRNA调控药物转运体和核受体表达^[107]。根据以上研究, 高原低氧环境中血脑屏障miRNA是否参与药物转运体和核受体表达调控, 影响药物跨血脑屏障转运还需进一步研究验证, 且低氧环境中血脑屏障miRNA表达变化及其与药物代谢间的联系有望成为诊断中枢神经系统疾病的新靶点。

3.2.5 肠道菌群

肠道菌群是影响药物体内生物转化的重要因素, 研究显示肠道菌群参与合成和释放γ-氨基丁酸、褪黑激素、儿茶酚胺、组胺、乙酰胆碱、血清素、犬尿氨酸等, 这些神经活性分子和炎症因子通过血液进入血脑屏障, 参与中枢神经系统药物代谢过程^[108]。Li等^[109]将酪酸梭菌定植于无菌小鼠后紧密连接相关蛋白上调, 血脑屏障通透性降低。Welcome^[110]发现肠道菌群紊乱使变形杆菌等致病菌促进毒性物质和炎症因子产生, 造成肠屏障损伤, 激活肠神经系统, 引起脑肠轴功能紊乱和血脑屏障功能障碍, 引发中枢神经系统炎症反应。Yang等^[111]研究表明低氧通过诱导信号分子, 向脑肠轴提供反馈, 使肠道菌紊乱和中枢神经系统功能障碍, 表明脑肠轴或可成为影响血脑屏障转运内源性物质的重要通道。课题组研究发现高原低氧环境中厚壁菌、阿克曼菌和乳杆菌等菌群紊乱调节药物代谢酶和药物转运体转录, 影响药物代谢^{[112, 113]}。以上研究显示, 肠道菌群作为机体重要的调控参与者是中枢神经系统疾病的易感因素, 低氧环境中特征性菌群紊乱可通过激活脑肠轴途径间接引起血脑屏障结构和功能变化, 参与药物代谢酶和药物转运体调节, 影响中枢神经系统药物转运。

高原低氧环境中, 血脑屏障结构和功能变化是否通过转录因子、炎症因子、核受体、miRNA和肠道菌群等相互作用影响药物代谢和转运亟需探究与验证。综上, 作者推测了以下五种分子机制: ①低氧环境激活转录因子和炎症因子, 使紧密连接相关蛋白重排并磷酸化, 引发血脑屏障结构和功能障碍, 药物转运体和药物代谢酶功能和表达变化。②高原低氧导致Mfsd2a水平失调, 增加胞吞作用和血脑屏障通透性, 改变药物转运体和药物代谢酶的功能和表达, 影响药物转运。③高原低氧增加血脑屏障通透性和诱导NF-κB信号通路, 调节核受体表达, 转录调控药物转运体和药物代谢酶, 影响药物转运。④高原低氧上调或下调血脑屏障中关键性miRNA表达, 直接或间接参与药物转运体或核受体调控, 使药物跨屏障转运发生变化。⑤高原低氧环境中特征性菌群紊乱使肠上皮细胞通过上行途径向中枢神经系统传递信号, 导致脑肠轴功能障碍及血脑屏障结构和功能变化, 间接参与药物代谢酶和药物转运体调节, 影响中枢神经系统药物转运, 如图 4。

4 小结与展望

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高原低氧环境对机体物质代谢具有显著影响, 阻碍机体中枢神经系统正常功能, 导致药物在体内的药物代谢动力学特征、药物转运体和药物代谢酶的活性与表达发生变化, 进一步影响药物疗效。研究高原低氧环境中药物跨血脑屏障转运的调节作用及机制, 可以促进中枢神经系统药物转运, 提升药物疗效, 避免不良反应的发生。此外, 探究高原低氧环境调节中枢神经系统药物转运的靶点, 可以为新药研发和高原地区中枢神经系统临床合理用药提供新的理论依据。

近年来, 人类高原活动日渐频繁, 高原旅游、商贸、体育训练等人群日益增多, 急进高原引起的头晕、头痛、共济失调、颅内压升高和脑水肿等中枢神经系统疾病严重威胁人类健康。充分了解低氧环境中枢神经系统解剖、生理病理变化, 对临床认识和治疗中枢神经系统疾病有很大帮助。大多数研究者把目光投向中枢神经系统的特异性细胞—神经元, 但低氧环境在引起神经元损伤前, 血脑屏障通透性增加或功能异常早已发生, 且血脑屏障变化与药物转运密不可分。因此, 研究高原低氧环境中血脑屏障结构和功能及其分子机制变化不乏成为高原地区中枢神经系统临床合理用药和疾病治疗的关键, 这同样也是中枢神经系统药物开发亟待解决的难题。

低氧环境诱导的血脑屏障结构和功能异常可通过屏障通透性变化指导中枢神经系统用药, 但单纯通过低氧促进或抑制药物进入血脑屏障减少或增加用药量, 虽具有一定用药指导意义, 但改变后的用药量将对脑组织或机体其他组织产生毒副作用。目前, 大量动物实验表明低氧增加血脑屏障通透性, 影响药物正常转运过程, 药物转运涉及屏障物理类、运输类和代谢类等转运系统。据此推断, 高原低氧环境中血脑屏障经历各种生理病理变化, 并通过多种调节机制影响药物转运系统, 这种调节包括屏障结构和功能、药代动力学特征、药物转运体和药物代谢酶等变化, 其中药物转运体和药物代谢酶作为调节药物代谢重要因素, 对中枢神经系统药物转运起关键和核心作用。

血脑屏障中药物转运体限制药物进入中枢神经系统, 成为中枢神经系统药物转运的巨大障碍, 许多研究都集中于开发抑制剂或发现调节信号通路, 如开发P-gp的抑制剂或将药物修饰成类似于P-gp底物的结构, 被血脑屏障P-gp识别后, 促进药物向中枢神经系统转运^[8]。这些策略不仅可抑制药物转运体的功能和表达升高, 还有效降低了游离药物浓度, 减轻脱靶效应, 提高中枢神经系统药物疗效。因此, 了解药物转运体在血脑屏障的调节机制有助于促进大脑对中枢神经系统药物的摄取, 提升药物有效性。血脑屏障中药物代谢酶影响中枢神经系统药物代谢和处置, 在减少大脑药物蓄积中发挥重要作用, 明确血脑屏障药物代谢酶的调控途径可为屏障通透性调节和药物转运提供参考依据。然而, 作者对高原低氧环境中血脑屏障药物转运体和药物代谢酶的表达和调节机制及它们与中枢神经系统疾病间关系的了解尚未全面, 且血脑屏障药物转运体作为多种中枢神经系统疾病治疗靶点的体内和体外研究数据十分有限。

本课题组前期研究表明高原低氧环境对大鼠血液、肝脏、肠道中的药物代谢动力学、药物代谢酶和药物转运体具有一定影响, 但低氧环境下血脑屏障与药物代谢的研究还鲜有报道, 且血脑屏障介导高原低氧对药物代谢的影响是通过药物转运体和药物代谢酶、转录因子、炎症因子及核受体等多因素调控的机制, 其表达变化是抑制还是促进药物跨血脑屏障转运尚未有定论, 仍需大量实验进行验证。明确血脑屏障介导高原低氧对中枢神经系统药物转运的影响虽具有挑战性, 但对高原地区血脑屏障结构和功能变化的认识, 有助于解释脑部疾病的诊断和预后以及制定合理的药理和非药理干预策略, 促进中枢神经系统药物向血脑屏障转运。另外, 研究高原低氧环境下血脑屏障变化与药物代谢的联系, 对高原人群中枢神经系统临床用药重新评估给药剂量, 制定符合高原地区的中枢神经系统用药标准具有重要意义。

综上, 高原低氧环境中血脑屏障变化与药物代谢间的关系对药物转运具有十分重要的作用和意义, 深入研究血脑屏障在高原低氧环境中与药物代谢之间的关系可为高原地区的人群提供更有效和更安全的药物治疗。

作者贡献: 李向阳、刘贵琴撰写稿件并总结图表; 白雪、杨建鑫、段雅彬负责论文内容核对; 朱俊博、田露参与论文相关内容补充。

利益冲突: 无任何利益冲突。

基金

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国家自然科学基金资助项目(82260731)
青海省创新平台建设专项(2021-ZJ-T03)

参考文献

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文献

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2023年第58卷第3期

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doi: 10.16438/j.0513-4870.2022-1095

接收时间：2022-10-05
首发时间：2025-11-21
出版时间：2023-03-12

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收稿日期：2022-10-05
修回日期：2022-12-17

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国家自然科学基金资助项目(82260731)

青海省创新平台建设专项(2021-ZJ-T03)

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1.青海大学高原医学研究中心, 青海西宁 810001

2.青海大学附属医院, 青海西宁 810001

3.青海大学医学院, 青海西宁 810001

4.青海大学三江源生态与高原农牧业国家重点实验室, 青海西宁 810016

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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Disease	Blood-brain barrier	Drug transporter	Drug metabolizing enzyme	Ref.
Multiple sclerosis	Tight junctions related protein expression changed	P-gp, ↓ BCRP, ↓ MRP1, ↓	CYP2B6 CYP2C9 CYP27B1 CYP2R1	[13-16]
Traumatic brain injury	Claudin-5, ↓ Caveolin-1, ↑	P-gp, ↓ Mfsd2a (possible), ↓	CYP1B1 CYP1A21 CYP2B1 CYP2D1 CYP3A2	[17-21]
Parkinson's disease	ZO-1, ↓ Occludin, ↓	P-gp, ↓ MRP2, ↑	CYP2D6 CYP2C19 CYP2B6 CYP1A2	[22-27]
Alzheimer's disease	Tight junctions abnormal	P-gp, ↓ MRP1, ↓ BCRP, ↑ MRP4, ↑ OATP2B1, ↓ Mfsd2a (possible), ↓	CYP3A CYP2D6	[17, 28-33]
Epilepsy	Tight junctions related protein expression changed	P-gp, ↑ BCRP, ↑ MRP1, ↑ MRP2, ↑	CYP3A4 CYP3A5 CYP2B6 CYP2D6	[16, 17, 34-37]
Stroke	Claudin-5, ↓ ZO-1, ↓ Caveolin-1, ↑	P-gp, ↑ MRP4, ↑ BCRP, ↑ MRP1, ↓ OATP1A2, ↑ Mfsd2a (possible), ↓	CYP2C19	[34, 38-43]
Brain tumor	ZO-1, ↓ Claudin-5, ↓	P-gp, ↑ BCRP, ↑ Mfsd2a (possible), ↓	CYP46A1 CYP1B1 CYP3A4	[17, 44-47]

Disease

Blood-brain barrier

Drug transporter

Drug metabolizing enzyme

Ref.

Multiple sclerosis

Tight junctions related protein expression changed

P-gp, ↓
BCRP, ↓
MRP1, ↓

CYP2B6
CYP2C9
CYP27B1
CYP2R1

[13-16]

Traumatic brain injury

Claudin-5, ↓
Caveolin-1, ↑

P-gp, ↓
Mfsd2a
(possible), ↓

CYP1B1
CYP1A21
CYP2B1
CYP2D1
CYP3A2

[17-21]

Parkinson's disease

ZO-1, ↓
Occludin, ↓

P-gp, ↓
MRP2, ↑

CYP2D6
CYP2C19
CYP2B6
CYP1A2

[22-27]

Alzheimer's disease

Tight junctions abnormal

P-gp, ↓
MRP1, ↓
BCRP, ↑
MRP4, ↑
OATP2B1, ↓
Mfsd2a
(possible), ↓

CYP3A
CYP2D6

[17, 28-33]

Epilepsy

Tight junctions related protein expression changed

P-gp, ↑
BCRP, ↑
MRP1, ↑
MRP2, ↑

CYP3A4
CYP3A5
CYP2B6
CYP2D6

[16, 17, 34-37]

Stroke

Claudin-5, ↓
ZO-1, ↓
Caveolin-1, ↑

P-gp, ↑
MRP4, ↑
BCRP, ↑
MRP1, ↓
OATP1A2, ↑
Mfsd2a
(possible), ↓

CYP2C19

[34, 38-43]

Brain tumor

ZO-1, ↓
Claudin-5, ↓

P-gp, ↑
BCRP, ↑
Mfsd2a
(possible), ↓

CYP46A1
CYP1B1
CYP3A4

[17, 44-47]

Blood-brain barrier	Drug transporter	Drug metabolizing enzyme	Ref.
ZO-1, ↓ Claudin-5, ↓ Occludin, ↓ Caveolin-1, － Increased permeability	Mfsd2a (possible), ↓ P-gp, ↑ BCRP, ↓ MRP-1, ↑ OATP1A4, ↑ OAT, － OCT, － GLUT1, ↑	CYP1A1, ↓ CYP1B1, ↓ CYP2C11, ↑ CYP46A1, ↑ UGT1A1, － GST, ↑	[49-51] [66, 69-71, 73, 74] [79-81, 84, 85]

Blood-brain barrier

Drug transporter

Drug metabolizing enzyme

Ref.

ZO-1, ↓
Claudin-5, ↓
Occludin, ↓
Caveolin-1, －
Increased permeability

Mfsd2a (possible), ↓
P-gp, ↑
BCRP, ↓
MRP-1, ↑
OATP1A4, ↑
OAT, －
OCT, －
GLUT1, ↑

CYP1A1, ↓
CYP1B1, ↓
CYP2C11, ↑
CYP46A1, ↑
UGT1A1, －
GST, ↑

[49-51]
[66, 69-71, 73, 74]
[79-81, 84, 85]