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二氯乙酸钠（sodium dichloroacetate，DCA）是一种小分子化合物，临床上常用于治疗乳酸酸中毒（lactic acidosis，LA）等疾病，可静脉注射或口服。研究表明DCA在体液中能完全电离，可更好的透过血脑屏障，在脑内达到有效治疗浓度[1]；此外，DCA可促进乳酸氧化，改善缺氧组织的能量代谢状况，故有望成为治疗心脑血管疾病的新型药物[2]。Moore等[3]的研究亦表明，DCA能作用于肿瘤细胞能量代谢途径，促进肿瘤细胞的氧化磷酸化，激活内源性凋亡通路，抑制肿瘤生长，在治疗肿瘤方面具有潜在应用价值。除开展DCA药品临床研究外，国际癌症研究机构（IRAC）于2014年报道称饮用水在氯化消毒过程中也会产生少量DCA[4]。因此，有关DCA的毒理与安全性研究则主要从药物毒理学以及环境毒理学两个领域展开，以评价其对人体健康的影响。本文拟从DCA的作用机制、临床应用及有关研究、毒理学研究等方面综述其近年的国内外研究进展，期望能为DCA综合开发利用提供参考。
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丙酮酸脱氢酶复合物（pyruvate dehydrogenase complex，PDC）是一组限速酶，在葡萄糖和丙酮酸氧化过程中，PDC催化丙酮酸氧化脱羧转化成乙酰辅酶A。乙酰辅酶A通过三羧酸循环和氧化磷酸化释放能量，推动ATP合成。PDC可将糖的有氧氧化与三羧酸循环和氧化磷酸化互相连接起来，有效地作用于细胞线粒体呼吸链能量代谢途径[1-3]。
DCA是PDC的激动剂，可与丙酮酸脱氢酶激酶（pyruvate dehydrogenase kinases，PDK）结合，抑制PDK活性，进而激活PDC[5-6]。研究表明DCA激活PDC后主要通过以下途径发挥作用：①加速丙酮酸氧化，阻断肝脏肌肉间的乳酸循环和丙氨酸循环；②阻止乳酸、丙氨酸从肌肉组织中释放；③促进外周组织对氧的摄取，催化外周组织对葡萄糖、乳酸的氧化；④抑制丙酮酸羧化酶，阻断肝脏糖异生通路[7-9]。如DCA在代谢性疾病的治疗中，主要通过促进乳酸氧化，降低血乳酸水平，进而改善机体的酸碱代谢平衡，缓解酸中毒症状。在治疗心脑血管疾病时，机体组织因缺血、缺氧导致血乳酸水平升高，DCA可通过增加氧摄取、激动PDC，促进乳酸氧化，补充能量供应，从而改善机体组织的能量代谢状况[2]。在肿瘤细胞能量代谢途径中，DCA可通过激活PDC降低丙酮酸和乳酸水平，诱导肿瘤细胞凋亡，进而抑制肿瘤生长[5]。然而，DCA是否还作用于其他机制，尚待进一步研究。
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脂质代谢紊乱是指先天或后天因素造成的血液及其他组织器官中脂质（脂类）及其代谢产物异常，通常表现为脂蛋白的异常。例如高脂蛋白血症是指血浆中乳糜微粒（CM）、极低密度脂蛋白（VLDL）、低密度脂蛋白（LDL）、高密度脂蛋白（HDL）等脂蛋白有一类或几类浓度过高的现象。
研究表明，DCA可降低高脂蛋白血症（Ⅱb、Ⅳ或V型）动物血清中三酰甘油的水平[2]，但其作用机制尚不清楚。此外，高脂蛋白血症患者口服DCA后，其血清中的胆固醇、三酰甘油和VLDL水平显著降低[10]。作为羟甲基戊二酰辅酶A（大鼠肝脏和人单核细胞中胆固醇合成限速酶）的非竞争性抑制剂，研究发现服用DCA后，有2名家族性高胆固醇血症患者（LDL受体阴性的纯合型）体内总胆固醇和LDL的水平均出现降低[3,11]。
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乳酸酸中毒（lactic acidosis，LA）是一种较少见却严重的糖尿病并发症。临床上，DCA可显著降低患者的乳酸水平，广泛应用于治疗LA患者[3,9]。尽管DCA并不能根治该病，但就其缓解酸中毒症状、改善血液动力学指标和控制患者并发症的效果而言，DCA比碳酸氢钠具有更良好的治疗效果[12]。
先天性乳酸酸中毒（congenital lactic acidosis，CLA）常发生于新生儿或婴儿期，PDC功能丧失是患儿出现CLA最常见的病因之一。研究表明患有CLA的新生儿对DCA的耐受性良好，经DCA治疗后，患儿血液和脑脊液中乳酸浓度显著降低[13-14]。来自开放标签的随机临床试验结果表明，儿童和成人患者口服DCA后，体内乳酸水平显著降低[3,12-15]。除了用于治疗CLA，DCA还可降低后天性LA成人患者的乳酸水平，调节其体内酸碱平衡，从而达到治疗效果[12,15-17]。
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心脑血管疾病是全身性血管病变或系统性血管病变，主要表现在心脏和脑部。研究表明，在机体组织因缺血缺氧导致血液乳酸水平升高时，DCA可通过增加氧摄取、激动PDC，促进乳酸氧化，调节机体的酸碱代谢平衡，补充能量供应，从而改善机体组织能量代谢状况；此外，DCA还可高效透过血脑屏障，在脑内能达到有效治疗浓度，可更好的用于治疗心脑血管疾病。心肌能量代谢改变是发生心肌缺血的重要因素。在葡萄糖氧化供能不足的情况下，DCA通过促进心肌中糖类和乳酸盐的代谢，显著改善缺血部位的能量代谢及功能[2]，缓解症状。动物实验结果表明，DCA可降低亨廷顿病小鼠脑中的乳酸含量[18]，改善动物的脑缺血损伤[19]，缓解由中枢神经系统缺血引起的LA症状[20]。
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德国著名学者Warburg提出肿瘤组织即使在有氧条件下也倾向于利用糖酵解来进行能量代谢，这一现象被称为“Warburg效应”。即在有氧的情况下，因细胞线粒体感受氧的能力下降，使得线粒体中有氧呼吸作用受到抑制，从而导致葡萄糖由有氧氧化向有氧糖酵解转变的过程。研究表明，DCA通过抑制PDKs重新激活PDC，降低丙酮酸和乳酸水平，诱导凋亡，从而抑制肿瘤生长[21]。基于DCA通过逆转Warburg效应进而诱导肿瘤细胞凋亡的分子机制，有学者提出在临床上使用DCA治疗实体瘤的研究方案[22]。四项开放标签Ⅰ期临床试验表明，恶性脑肿瘤或其他成人慢性实体肿瘤患者口服DCA[12.5～25 mg/（kg·d）]耐受性良好，但个别患者出现外周神经系统症状，这一症状会伴随给药剂量减少或停药后自行消失[23-26]。虽然近年来一直有文献报道，DCA及其衍生物有望用于治疗肿瘤相关疾病[21,27]，但是有关DCA治疗肿瘤有效性的结果仍鲜有报道[28]，其治疗效果与作用机制仍待进一步观察与研究。
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（1） Mitaplatin衍生物：Mitaplatin是一种新的铂化合物，由顺铂与DCA结合而成。该铂化合物进入细胞后，通过释放顺铂和DCA，可有效攻击细胞核和线粒体，进而杀死癌细胞。研究表明，当正常成纤维细胞与癌细胞混合培养时，此种衍生物能选择性地杀死癌细胞而不影响正常成纤维细胞的活力[29]。
（2） Bet-CA衍生物：Bet-CA衍生物是将桦木酸和DCA相结合的化合物，其中桦木酸是一种具有独特抗癌活性的天然产物。体外研究表明，当癌细胞与人成纤维细胞共培养时，Bet-CA可选择性地杀死癌细胞[30]。体内实验证明Bet-CA具有抗肿瘤特性，可有选择地协同对抗癌症而不产生毒性，有望成为新一代抗癌药物[31]。
（3） Mito-DCA衍生物：Mito-DCA衍生物是小分子PDK抑制剂，可改变肿瘤细胞的能量代谢途径，即从糖酵解转换为葡萄糖氧化，进而诱导细胞凋亡[32]。与DCA相比，Mito-DCA的效力和肿瘤细胞特异性均提高了3个数量级，具有更好的抗癌作用。此外，Mito-DCA对肿瘤细胞线粒体的特异性也更高，能更充分的发挥DCA的抗癌作用，而不影响正常细胞的新陈代谢[33-34]。
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研究表明，Warburg效应和一个或多个PDK启动子，可作为某些疾病的潜在治疗靶点[35-38]，如自身免疫性疾病、阻塞性肺疾病、冠状动脉再狭窄和肌萎缩侧索硬化（amyotrophic lateral sclerosis，ALS）等。ALS小鼠体内常出现Warburg效应，同时伴随PDK的激活和PDC的磷酸化[39-40]。未来，DCA可能代表一类新的代谢调节剂，此类调节剂将在细胞代谢的关键结合部位和作用靶点上发挥重要调节作用。
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美国国家毒理学计划（NTP）[41]和IARC[42]已将DCA的毒理学特性纳入评估范围。目前大多数有关DCA动物毒理学研究，其给药剂量更接近于临床使用范围，并非环境中的暴露剂量，如生活饮用水中DCA的浓度一般为0.3～100 μg/L[4]。暂无有关暴露于饮用水中的DCA与疾病的关联性研究[1]。Stacpoole等[43]分析了DCA对动物的毒性作用，其作用的靶器官包括肝脏、肾脏、神经系统等。动物实验研究表明，当DCA的口服给药剂量达到临床使用范围水平，可诱发肿瘤、肝细胞损伤、神经毒性等[43-47]。
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基于DCA的抗癌特性，研究人员对实验大鼠和小鼠进行慢性毒性测试，结果显示，持续饮用高剂量（5 g/L）DCA的动物，其肝脏于76～104周发生癌变[44]，持续52周饮用剂量低于0.5 g/L的DCA，动物体内未出现肿瘤[45]。此外，少数线粒体疾病患者服用DCA长达20年，患者体内并未出现肿瘤样病变[17]。因此，IARC于2004年得出结论：DCA对人类致癌性证据不足，但对实验动物致癌性证据充足[41]。
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肝脏慢性毒性测试结果显示，DCA给药后患者会出现轻微但可逆的转氨酶升高[46]。然而，原发性线粒体疾病的受试者长期口服DCA剂量高达25 mg/（kg·d）数年，患者体内血清转氨酶、血液学、代谢、肾或肝功能的任何指标均无显著变化[17]。目前现有研究结果仍无法明确DCA对肝脏的毒性，需进一步完善相关毒性测试。
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接受长期DCA治疗的患者最易受到影响的是神经系统。研究表明，健康成人志愿者多次口服或静脉注射DCA 25～50 mg/（kg·d）后，周围神经病变的检出率约为50%，志愿者通常在给药后60 min内会出现疲倦、镇静等症状，并可能持续数小时[43,47]。患有CLA的儿童，连续数月口服DCA 50～100 mg/（kg·d）亦出现可逆的周围神经病变[43]。一般症状在降低剂量或停药后可自行消失。目前慢性DCA治疗所引起的可逆性外周神经病变，是限制临床使用DCA的主要因素[47-48]。
Medical research progresses on sodium dichloroacetate
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摘要: 二氯乙酸钠（DCA）是一种常用于口服的小分子化合物，临床上常用于治疗乳酸酸中毒（LA）等疾病，可静脉注射或口服。目前DCA对代谢性疾病、心脑血管疾病及几种实体瘤等均具有良好的治疗作用。结合近年来国内外有关DCA药理作用的文献，从作用机制、临床应用及毒理学研究等3个方面对DCA的医学研究进展进行综述。Abstract: Sodium dichloroacetate (DCA) is a small molecule drug usually administered orally. It has therapeutic effects against several diseases, such as metabolic syndrome, cardiovascular and cerebrovascular diseases, and several solid tumors. In this review, the research progresses of DCA in mechanism of action, pharmacological action and toxicological studies were summarized from the recent literatures on the pharmacological actions of DCA.
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Key words:
- sodium dichloroacetate /
- pharmacology /
- derivatives /
- toxicological studies
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