2016, Vol. 51
药物转运体是位于细胞膜上的功能性膜蛋白,在药物或化学异物的吸收、分布、代谢和排泄等体内过程中起非常重要的作用,是影响药物效应及产生药物-药物相互作用的重要因素。药物转运体主要分为可溶性物质载体 (solute carrier,SLC) 和ATP结合盒转运体 (ATP binding cassette,ABC)。
ABC转运体是由49个已知基因结构的家族成员构成的蛋白超家族,包括P-糖蛋白 (P-glycoprotein,P-gp)、多药耐药相关蛋白 (multidrug resistance protein,MRP1) 和乳腺癌耐药蛋白 (breast cancer resistance protein,BCRP) 等,主要发挥外排转运的作用[1, 2]。
BCRP是继P-gp和MRP1耐药蛋白之后发现的第三大外排转运蛋白[3]。作为外排性转运体,BCRP在机体中分布广泛,作用底物多样,不仅是引起肿瘤化疗药物耐药的重要因素,也影响其他非抗癌药的体内过程。鉴于其对药物代谢动力学的重要作用,CFDA、FDA等均建议在进行新药的临床申报时,应研究该化合物与BCRP转运体的相互作用。
自1998年BCRP转运体被发现以来,国内外已有许多相关文章发表,发现数百种药物或化学异物均为BCRP转运体的底物或抑制剂[4]。本文从BCRP转运体的发现、生理功能和转运机制、底物和抑制剂以及对药物代谢动力学特征的影响等方面总结了关于BCRP转运体的最新研究进展,以期为药物转运体BCRP与药物代谢动力学的研究提供借鉴。
1 BCRP的发现药物转运体介导的药物外排是引起多药耐药的重要因素。19世纪70年代,人们普遍认为P-gp和MRP1是产生药物耐药现象的主要外排蛋白。直到20世纪末,Ross等[5]从白血病患者体内发现一种新型耐药细胞,而P-gp和MRP1都不是引起该细胞株耐药的原因。Doyle等[6]进一步分离得到一种新的依赖ATP的转运蛋白,由于是从乳腺癌耐药细胞株 (drug- resistant breast cancer cell) MCF/AdrVp细胞株中发 现的,因此命名为BCRP。同时,另外两个实验室的Allikmets等[7]和Miyake等[8]也分别从人胎盘细胞 (human placenta cell) 和米托蒽醌耐药细胞株 (mitoxantrone-resistant cell) 中分离到该蛋白,因此又被命名为ABCP和MXR。BCRP、ABCP和MXR都是指同一种转运蛋白,只是个别位点的氨基酸不同。另外,BCRP的编码基因为ABC转运体超家族中G亚家族的第二个成员,因此又被称为ABCG2。为区别人和其他种属,人乳腺癌耐药蛋白命名为BCRP/ABCG2,啮齿类动物 (大鼠/小鼠) 乳腺癌耐药蛋白命名为Bcrp/Abcg2。
多个BCRP转染细胞研究表明其与某些抗癌药物的多药耐药程度高度相关,减少抗癌药物在细胞中的累积量,提示BCRP是特定类型抗癌药物耐药的耐药蛋白[9-13]。BCRP存在于体内多个重要器官,如小肠、胎盘、肝脏、肾脏等,对药物的吸收 (小肠)、分布 (胎盘)、代谢 (肝脏) 和排泄 (肾脏) 具有重要意义。
2 BCRP的组织分布了解药物转运体在不同组织中的分布趋势,有助于预测和解释药物在体内的吸收、分布、代谢和排泄过程。Maliepaard等[14]首次对BCRP转运体在人 体正常组织中的表达进行了研究,结果表明BCRP 转运体在胎盘合胞体滋养层 (placental syncytiotrophoblasts) 表达量最高,小肠和结肠上皮细胞顶侧膜 (apical membrane) 以及肝胆小管膜次之。Huls等[15]报道BCRP在人肾近曲小管细胞顶侧膜也有表达,不过表达量明显低于小肠和肝组织。随着研究的深入,人们逐渐发现BCRP在视网膜毛细血管内皮细胞和各种血-组织屏障 (blood-tissue barriers) 如血脑屏障 (blood-brain barriers)、血睾屏障 (blood-testis barriers)、血-胎盘屏障 (blood-placental barriers) 和血脊髓屏障(blood-spinal cord barriers) 中也有表达[16-19]。与人相比,小鼠肾组织中BCRP表达量较高,胎盘表达水平一般,存在一定的种属差异[20]。
3 BCRP的生理结构及转运机制BCRP是分子质量为72 kD的跨膜蛋白,由655个氨基酸组成,编码基因为ABCG2。由于BCRP只有1个核苷酸结合区 (nucleotide binding domain,NBD) 和1个6次跨膜区 (transmembrane domain,TMD),因此,又被称为半转运体 (half-transporter) BCRP[6]。此外,和大多数ABC转运体的结构相反,BCRP转运体的ATP结合部位在 -NH2端,跨膜区在 -COOH端(图 1)[21]。由于ABC转运体发挥转运功能需要两个NBD结构,因此,BCRP常以二聚体或多聚体的形式存在[22-24]。研究表明,BCRP多聚体的形成与603位半胱氨酸形成二硫键有关[25, 26]。BCRP结构中只有一个N糖基化结合位点,即位于5,6跨膜结构域的596位天冬氨酸 (Asp)[27]。
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Figure 1 The membrane topology model of transporter breast cancer resistance protein (BCRP) |
作为ABC转运体家族的一员,BCRP与P-gp类似,也是利用ATP水解提供能量,将底物从细胞内转运至细胞外。NBD负责结合ATP; TMD作为底物的结合部位,决定转运底物的特异性。与P-gp转运机制不同的是,BCRP进行转运时需要由二硫键形成二聚体或多聚体[28]。
一般来说,ABC转运体均具有多个底物的结合位点。由于目前尚未获得高分辨率的BCRP 3D结构,人们对BCRP与底物的结合位点知之甚少。Mao等[29]报道Arg482和Pro485可影响BCRP对部分底物的转运,但对于是直接影响与底物的结合,还是间接通过稳定结构或诱导构象改变而影响BCRP与底物的结合还需要进一步确认。Clark等[30]通过亲和动力学研究发现米托蒽醌和哌唑嗪与BCRP的结合位点明显不同。Giri等[31]通过对BCRP与抑制剂的相互作用研究证实,齐多夫定和阿巴卡韦与BCRP的结合位点与哌唑嗪不完全重合。有学者[32]应用BCRP的同源模型推测,BCRP 6次跨膜区域形成的内部空腔足以适应多种底物与BCRP的结合,但是BCRP的准确结合位点还需高分辨的BCRP 3D结构进行确认。
4 BCRP的底物和抑制剂 4.1 BCRP的底物自BCRP转运体发现以来,已知底物超过200个,代表性经典底物见表 1[33-57]。由于BCRP发现于肿瘤耐药细胞,因此最初报道的BCRP底物大多是经典的肿瘤化疗药物,如米托蒽醌 (mitoxantrone)、喜树碱衍生物 (camptothecin derivates)、甲氨蝶呤 (methotrexate) 等。米托蒽醌是最早发现的经典BCRP底物,常被用来做为研究BCRP转运体的阳性对照药[20, 33, 34]。喜树碱衍生物包括喜 树碱类抗肿瘤药如拓扑替康 (topotecan)、伊立替康 (irinotecan)、SN-38 (伊立替康活性代谢产物) 等。上述药物在肿瘤细胞的耐药性与BCRP的表达水平密切相关[36-38]。需要指出的是,喜树碱本身以及其类似物包括DX9851f和9-硝基喜树碱却不是BCRP的 转运底物[37, 58, 59]。随着BCRP转运体的深入研究,更多的化疗药物被发现是BCRP的底物,如酪氨酸激 酶抑制剂 (tyrosine kinase inhibitors,TKIs): 伊马替尼 (imatinib); 光敏剂 (photosensitizers): 脱镁叶绿酸A (pheophorbide A,PhA)、原卟啉IX (protoporphyrin) 等[40-42]。
当然,BCRP转运体的底物不仅仅限于肿瘤治 疗药,部分非肿瘤治疗药物也是其底物。包括一些 抗病毒药 (antivirals)、调血脂药 (statins)、抗生素 (antibiotics)、钙离子通道阻滞剂 (calcium channel blockers) 如齐多夫定、西伐他汀、环丙沙星、尼群地平等[43, 48, 50, 60]。除此之外,某些荧光探针也是BCRP的底物,如BODIPY-FL prazosin、Hoechst 33342、PhA等,可作为体外研究BCRP转运体活性的重要工具[41, 61, 62]。
BCRP个别位点的氨基酸突变可影响其转运底物的特异性。蒽环霉素 (anthracycline) 在BCRP高表达的MCF-7/AdrVp3000细胞株和S1-M1-80细胞株中高度耐药,而在其他10种BCRP高表达的细胞株中则无耐药现象[63]。进一步研究发现,MCF-7/AdrVp3000细胞中BCRP cDNA编码的482号氨基酸为Thr,S1-M1-80为Gly (均为突变型),而在其他癌细胞和正常细胞中为Arg (野生型)。值得一提的是,罗丹明123 (rhodamine 123) 和Lysotracker只是突变型BCRP的底物,而非野生型BCRP的底物[64]。
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Table 1 Summary of substrates of BCRP |
虽然目前已发现200余种BCRP转运体的底物,但是人们对BCRP转运体与底物之间的构效关系 (structure-activity relationship,SAR) 却不甚明了。BCRP与喜树碱类化合物相互作用的SAR研究发现,喜树碱类化合物C-10和C-11的极性越大,与BCRP转运体的亲和力越强[65]。Hazai等[66]根据已知263个BCRP底物运用support vector machine (SVM) 方法构建了BCRP底物的预测模型,准确率约为76%。
4.2 BCRP的抑制剂抑制剂是研究药物转运体的重要工具。对于大多数转运体来说,研究一个药物是否是转运体的底物,最常用的方法就是抑制剂法。因此,了解转运体抑制剂的类型和种类,对于研究药物与转运体的相互作用具有重要意义。
作为肿瘤多药耐药蛋白,以BCRP为靶标逆转多药耐药的抑制剂研究较为广泛。表 2[67-82]总结了部分经典抑制剂。烟曲霉毒素 (fumitremorgin C,FTC) 是第一个被发现的BCRP特异性抑制剂,从烟曲霉原变种 (Aspergillus fumigatus) 菌落中提取分离,IC50约为1 μmol·L-1 [67, 68]。然而,由于FTC具有较强的神 经毒作用,人们以其为先导物,发现了多种对BCRP有抑制作用的类似物,如Ko132、ko134和Ko143等(IC50为100～200 nmol·L-1)[69]。虽然Ko143在过去十几年中一直作为研究药物与BCRP相互作用的阳性对照药,但最近报道指出,Ko143并非BCRP转运体的特异性抑制剂,其对ABCB1和ABCC1也有一定抑制作用。因此,应用Ko143研究药物与BCRP转运体的相互作用时需考虑其特异性问题[83]。
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Table 2 Summary of inhibitors of BCRP. ND: Not detected |
自FTC发现以后,陆续发现了多个结构类型不同的BCRP转运体的抑制剂,包括新生霉素 (novobiocin)、三氧苯胺 (tamoxifen)、利托那韦 (ritonavir)、吉非替尼 (gefitinib) 等[72-75],均为BCRP的非特异性抑制剂。直到目前为止,还未有报道BCRP的特异性抑制剂。
根据BCRP转运体抑制剂的作用机制不同,可 分为以下3类: ① 抑制ATP酶活性,从而抑制BCRP转运活性,如FTC和Ko143; ② 抑制剂本身为BCRP的底物,竞争性抑制BCRP的转运,如双嘧达莫; ③ 抑制剂虽不是BCRP的底物,但可与BCRP结合而 改变其构象,进而影响BCRP的转运,如利托那 韦[51, 67, 75, 77]。由于BCRP有多个结合位点,因此②和③类抑制剂只抑制部分药物的转运。Giri等[31]发现 那非那韦 (nelfinavir) 可抑制BCRP对齐多夫定和阿巴卡韦的转运,但不抑制哌唑嗪和伊马替尼的转运。
与BCRP的底物研究不同,对BCRP与抑制剂的SAR和定量构效关系 (QSAR) 的研究较为深入[84-86]。黄酮类化合物和FTC类似物的亲脂性是抑制作用的关键因素[87, 88]。此外,抑制剂的平面结构、杂环上C-NH2键以及潜在的氢键对BCRP的抑制也有重要影响[86, 89]。有学者构建了不同SAR和QSAR模型用于预测BCRP的抑制剂,由于目前对BCRP与底物和抑制剂的相互作用机制还不是十分清楚,因此,上述模型只能进行内部数据集的预测[29]。
5 BCRP的单核苷酸多态性基因突变在自然界中普遍存在,药物转运体也不例外。基因突变会导致mRNA表达水平、翻译效率以及蛋白功能的改变。由于药物转运体对药物的 吸收、分布和排泄有重要影响,因此药物转运体的基因突变会引起底物药物在不同个体的药代动力学差异,最终影响药物的有效性和毒性。目前,人们已从人不同器官的DNA样品中发现了大约80种ABCG2基因的单核苷酸基因多态性 (SNPs)。其中,34G > A (V12M) 和421C > A(Q141K) 的突变频率最高,在东亚人群中约为30%～60%,而在高加索人和美洲人群中约为5%～10%。其他SNPs的发生频率均较低,约为1%[29]。有研究表明,421C > A导致的Q141K突变可引起细胞表面的BCRP表达减少,进而降低其外排活性; 而34G > A导致的V12M突变对BCRP表达以及耐药程度无明显影响[90, 91]。其他SNPs如114T > C,369C > T,474C > T,564A > G,1098G > A和1425A > G不引起氨基酸的改变,但是否会影响BCRP的表达和活性还未有报道[92]。
有学者研究了BCRP的SNPs与其底物药物的药物代谢动力学的相关性,发现421C > A的基因突变对他汀类药物如罗素伐他汀、氟伐他汀和辛伐他汀 的药物代谢动力学特征有重要影响。联合口服给药BCRP抑制剂GF120918后,上述他汀类药物在BCRP基因表型为421AA纯合子的受试者体内的AUC或Cmax明显升高,而在421CA杂合子受试者体内则无明显变化[93, 94]。
6 BCRP对药物体内过程的影响由上所述,BCRP转运体存在于体内多个重要组织,因此其对药物和化学异物在体内过程的各个环节: 吸收 (小肠)、分布 (胎盘)、消除 (肝脏和肾脏) 均可能有重要影响。
6.1 BCRP对药物口服生物利用度的影响Jonker等[95]报道,ABCB1/ABCG2双抑制剂依克利达 (GF120918) 可显著提高拓扑替康在mdr1a/mdr1b-/-小鼠的生物利用度,提示拓扑替康生物利用度的增加可能来自小肠部位吸收的增加和肝脏消除的减少。Yamagata等[96]发现,Abcg2基因敲除小鼠拓扑替康的吸收速率增加了2倍,体内暴露量增加了3.6倍,进一步证明了BCRP转运体对拓扑替康的口服生物利用度的作用。此后,应用基因敲除Abcg2小鼠的研究多次报道了BCRP转运体对药物或化学异物在小肠吸收的影响,如抗生素类药物、抗炎药柳氮磺胺嘧啶、CDK抑制剂JNJ-7706621等[97-99]。此外,BCRP还可影响多种食物成分的摄取,如2-氨基-3甲基咪唑并 [4,5-f] 喹啉 (IQ)、3-甲基-1,4二甲基-5H-吡啶并 [4,3-b] 吲哚 (Trp-P-1) 等[100]。
值得注意的是,尽管体外研究证明多种药物是BCRP的底物,但在Abcg2基因敲除小鼠模型未证 实BCRP对生物利用度的调节作用。如依托泊苷 (etoposide) 曾被多次报道为BCRP的底物,然而有 研究[101, 102]发现在Mdr1a/Mdr1b-/-小鼠中依克立达 (BCRP抑制剂) 对其口服生物利用度和清除率并无显著性影响。同样的药物还有抗艾滋病药物阿巴卡 韦和齐多夫定,其在野生和Abcg2-/-小鼠中的药代动力学参数无显著性差异[71]。
6.2 BCRP对药物透过血脑屏障的影响血脑屏障是药物或化学异物进入大脑的重要屏障,对大脑内环境稳定起重要的保护作用。BCRP在大脑微血管内皮细胞中的表达提示其可调节药物进入中枢系统。BCRP转运体特异性底物如单曲林、木黄酮、香豆雌酚等在Abcg2-/-小鼠中脑内的累积量明显高于野生型小鼠[103]。但是由于血脑屏障结构的复杂性以及存在多种药物转运体如P-糖蛋白、ABCB1等,BCRP对非特异性底物透过血脑屏障的作用机制比较复杂。如静脉注射伊马替尼后,与野生型小鼠相比,Abcg2-/-小鼠大脑透过量增加2.5倍,而Mdr1a/Mdr1b-/-小鼠大脑透过量增加3.6倍,提示BCRP和MDR1转运 体均对伊马替尼透过血脑屏障产生影响。然而在体 脑灌流实验发现,伊马替尼低浓度 ( < 1 μmol·L-1)
时,MDR1对其转运起主要作用,BCRP对其吸收几 乎没有影响。高浓度 (1～20 μmol·L-1) 时,BCRP 明显影响伊马替尼的吸收[104, 105]。又如野生型小鼠和Abcg2-/-小鼠短时间在体脑灌流致癌物1-氨基-1-甲基-6-苯咪基并[4,5-b]吡啶 (PhIP),脑内累积量无明显差异,而随灌流时间的延长,Abcg2-/-小鼠PhIP脑内累积量明显高于野生鼠[106]。BCRP转运体对药物或化学异物跨血脑屏障的影响与药物浓度、暴露时间以及药物或化学异物与转运体的亲和力密切相关。
6.3 BCRP对药物透过胎盘屏障的影响BCRP在胎盘绒毛合胞体滋胚层顶侧膜高表达,阻止药物或化学异物进入胎盘。Keskitalo等[93]首次报道了BCRP对拓扑替康通过胎盘屏障的影响。Mdr1a/Mdr1b-/-小鼠给予依克立达后,胎儿体内拓扑替康浓度增加两倍。Zhang等[107]发现静脉注射BCRP底物呋喃妥英后,Abcg2-/-受孕小鼠胎儿体内呋喃妥因浓度是野生受孕鼠的5倍。另外,BCRP转运体对抗糖尿病药格列本脲、致癌物PhIP和甲硝基二甲胺等透过胎盘屏障也有明显影响[108-110]。
6.4 BCRP对药物进入乳腺的影响与其他屏障作用相反,BCRP可增加药物或化学异物进入乳腺。Alcorn等[111]研究发现,野生型小鼠阿昔洛韦的血浆/母乳比为5∶1,而在Abcg2-/-小鼠中阿昔洛韦的乳腺累积量显著降低。同样,BCRP转运体也可增加西咪替丁、呋喃妥英和PhIP等在乳腺中的吸收[112-114]。
6.5 BCRP对药物肝脏胆汁排泄的影响已知BCRP表达于肝细胞的胆小管膜,提示可能影响药物的胆汁排泄[115]。研究报道,甲氨蝶呤在Abcg2-/-小鼠的清除率明显低于野生型小鼠,而7-OH甲氨蝶呤却无此现象[75, 116]; 抗血脂药匹伐他汀在Abcg2-/-小鼠的胆汁排泄量是野生型小鼠的1/10[117]。Sparreboom等[39]利用Abcg2-/-小鼠研究了BCRP转运体对喹诺酮类抗生素环丙沙星、格帕沙星、氧氟沙星和尤利沙星胆汁排泄的影响。
6.6 BCRP对临床药物相互作用的影响目前已有临床研究证实BCRP在药物-药物相互作用 (drug- drug interactions) 中的重要作用。Kruijtzer等[118]首 次报道联合口服给药GF120918后,拓扑替康的生物利用度由40% 增加到97%。近年来,人们又多次发 现临床上BCRP的底物药物与其抑制剂合用后,会 发生明显的DDIs,包括阿托伐他汀与利托那韦、罗素伐他汀与利托那韦、辛伐他汀与GSK1292263,甲氨蝶呤和奥美拉唑合用等[119-121]。
7 结语近年来,药物转运体对药物体内过程的影响一直是药物代谢动力学研究的热点之一。BCRP转运体作为ABC转运体家族中的重要一员,对药物的吸收、分布、代谢和排泄等过程都起着重要作用。然而,目前对于BCRP转运体的分子转运机制尚不完全明了。因此,获得高分辨率BCRP 3D结构,明确BCRP转运体与底物或抑制剂的SAR,构建计算机预测的BCRP底物或抑制剂模型都将有助于深入了解BCRP转运体在药物代谢动力学和药物-药物相互作用中的意义,为新药研发提供依据。
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