药学学报

Edition of the Chinese Pharmacopoeia	Deletion and revision of traditional Chinese medicinal materials varieties	Deletion and revision of Chinese patent medicine varieties	Reasons for deletion and revision
2005	Caulis Aristolochiae Manshuriensis, Radix Aristolochiae Fangchi, Radix Aristolochiae^[7], the medicinal part of Herba Asari was revised from "whole herb" to "root and rhizome"^[8]	All proprietary preparations containing Caulis Aristolochiae Manshuriensis, Radix Aristolochiae Fangchi, or Radix Aristolochiae were uniformly replaced with Caulis Akebiae (Lardizabalaceae), Radix Stephaniae Tetrandrae (Menispermaceae), and Radix Inulae (Asteraceae)^[8]	Based on high attention to drug safety and consideration of potential risks of hepatorenal toxicity^[9]
2010	None^[10]	None^[10]	No variety deletion was made in Volume I of this edition of the Pharmacopoeia
2015	Hominis Placenta^[11]	Pediatric Diarrhea External Powder, Shengxue Wan, Ankun Zanyu Wan, Heche Dazao Wan, Bushen Guchi Wan, Yixuesheng Capsule^[11]	Based on considerations of safety, efficacy, quality controllability^[12] and protection of endangered species^[13]
2020	Frucutus Aristolochiae, Herba Aristolochiae, Manis Squama^[14]	Huanglian Yanggan Wan^[14]	Based on considerations of wild resources, ethical issues^[15] and the results of special studies on the dose-effect relationship of traditional Chinese medicine components and toxicity^[16]
2025	None^[17]	Jiusheng San, Rongshuan Zaizao Wan, Xiaoying Wan, Wanling Wuxiang Gao, Guiling Ji, Tongru Keli, Zhisou Huatan Wan, Awen Huatan Gao, Tongpian Pian, Zaizao Wan, Badu Gao, Tongbi Jiaonang, Zhuye Datan Wan, Jinpu Jiaonang, Shexiang Naimaikang Jiaonang, Yangdan Wan, Huixiang Juhe Wan, Fuke Tongjing Wan, Huhun Wine^[17]	No longer include Chinese patent medicines using wild endangered animals and plants as raw materials, Chinese patent medicines that have not been used clinically for a long time without approval numbers, and Chinese patent medicines with potential safety issues^[18]

Edition of the Chinese Pharmacopoeia	Deletion and revision of traditional Chinese medicinal materials varieties	Deletion and revision of Chinese patent medicine varieties	Reasons for deletion and revision
2005	Caulis Aristolochiae Manshuriensis, Radix Aristolochiae Fangchi, Radix Aristolochiae^[7], the medicinal part of Herba Asari was revised from "whole herb" to "root and rhizome"^[8]	All proprietary preparations containing Caulis Aristolochiae Manshuriensis, Radix Aristolochiae Fangchi, or Radix Aristolochiae were uniformly replaced with Caulis Akebiae (Lardizabalaceae), Radix Stephaniae Tetrandrae (Menispermaceae), and Radix Inulae (Asteraceae)^[8]	Based on high attention to drug safety and consideration of potential risks of hepatorenal toxicity^[9]
2010	None^[10]	None^[10]	No variety deletion was made in Volume I of this edition of the Pharmacopoeia
2015	Hominis Placenta^[11]	Pediatric Diarrhea External Powder, Shengxue Wan, Ankun Zanyu Wan, Heche Dazao Wan, Bushen Guchi Wan, Yixuesheng Capsule^[11]	Based on considerations of safety, efficacy, quality controllability^[12] and protection of endangered species^[13]
2020	Frucutus Aristolochiae, Herba Aristolochiae, Manis Squama^[14]	Huanglian Yanggan Wan^[14]	Based on considerations of wild resources, ethical issues^[15] and the results of special studies on the dose-effect relationship of traditional Chinese medicine components and toxicity^[16]
2025	None^[17]	Jiusheng San, Rongshuan Zaizao Wan, Xiaoying Wan, Wanling Wuxiang Gao, Guiling Ji, Tongru Keli, Zhisou Huatan Wan, Awen Huatan Gao, Tongpian Pian, Zaizao Wan, Badu Gao, Tongbi Jiaonang, Zhuye Datan Wan, Jinpu Jiaonang, Shexiang Naimaikang Jiaonang, Yangdan Wan, Huixiang Juhe Wan, Fuke Tongjing Wan, Huhun Wine^[17]	No longer include Chinese patent medicines using wild endangered animals and plants as raw materials, Chinese patent medicines that have not been used clinically for a long time without approval numbers, and Chinese patent medicines with potential safety issues^[18]

现代生物技术在马兜铃等有毒中药中的应用前景刍议

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荣千漪 ¹^,² , 濮春娟 ¹^,²^,^* , 李琦爽 ³ , 郑汉 ³ , 王嘉成 ⁴ , 吴啟南 ¹^,²^,^*

药学学报 | 综述 2026,61(8): 2914-2929

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药学学报 |综述 2026 , 61 (8) : 2914 -2929

现代生物技术在马兜铃等有毒中药中的应用前景刍议

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荣千漪¹^,², 濮春娟¹^,²^,^*, 李琦爽³, 郑汉³, 王嘉成⁴, 吴啟南¹^,²^,^*

作者信息

¹南京中医药大学药学院, 江苏南京 210023

²江苏省中药资源产业化过程协同创新中心/中药资源产业化与方剂创新药物国家地方联合工程研究中心/国家中医药管理局中药资源循环利用重点研究室, 江苏南京 210023

³中国中医科学院, 道地药材品质保障与资源持续利用全国重点实验室, 北京 100700

⁴南京中医药大学第一临床学院, 江苏南京 210023

通讯作者:

濮春娟, E-mail: puchunjuan@njucm.edu.cn

吴啟南, E-mail: wuqn@njucm.edu.cn

作者简介:

作者贡献:

荣千漪负责相关文献检索、文章绘图及综述撰写; 李琦爽完成马兜铃酸生物合成途径的梳理与阐述; 郑汉对现代生物技术的应用策略提供指导; 王嘉成参与文献检索与图表制作; 濮春娟、吴啟南提出论文的构思, 全程指导综述的撰写。

A preliminary discussion on the application prospects of modern biotechnology in toxic Chinese medicines including Aristolochia

Qian-yi RONG¹^,², Chun-juan PU¹^,²^,^*, Qi-shuang LI³, Han ZHENG³, Jia-cheng WANG⁴, Qi-nan WU¹^,²^,^*

Affiliations

¹School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China

²Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Key Laboratory of Chinese Medicinal Resources Recycling Utilization of State Administration of Traditional Chinese Medicine, Nanjing 210023, China

³State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-Di Herbs, China Academy of Chinese Medical Sciences, Beijing 100700, China

⁴The First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing 210023, China

出版时间: 2026-08-12 doi: 10.16438/j.0513-4870.2026-0261

文章导航

摘要

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有毒中药是中医药体系的重要组成部分, 以含马兜铃酸的中药为例, 其临床应用与产业化发展因所含马兜铃酸类成分引发的安全性事件而面临严峻挑战。《中华人民共和国药典》基于药品安全性考虑删减相关品种, 虽规避用药风险, 却也造成药用资源的浪费。现有炮制、配伍等方法在此类中药的减毒中存在减毒效果有限、工艺难以标准化等局限, 且难以平衡毒性控制与药效保留。基于此, 本文系统梳理了近5版的中国药典中药材及中成药品种删减情况, 总结了马兜铃属来源中药的药用价值与争议、马兜铃酸的致毒机制、现有减毒方法及其局限性。针对上述局限, 立足现代生物技术视角, 提出基因编辑、酶工程、发酵工程等技术在马兜铃等中药减毒中的应用策略, 探讨精准调控毒性成分合成与降解的新路径。与传统减毒方法相比, 利用现代生物技术有望精准调控毒性成分的合成或降解, 在降低毒性的同时保留药材整体药效, 以期实现“减毒存效”。未来需强化有毒中药的基原考证、有毒成分的生源合成途径解析及其致毒机制研究, 开展有毒中药资源开发利用, 推动中医药传承创新与现代化、国际化高质量发展。

关键词

马兜铃酸 / 有毒中药 / 关木通 / 生物技术 / 减毒

Abstract

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Toxic Chinese medicines constitute a significant component of the traditional Chinese medicine system. Taking aristolochic acid-containing herbs as an example, their clinical application and industrial development face severe challenges due to safety incidents caused by aristolochic acid-containing components. The Pharmacopoeia of the People's Republic of China has deleted relevant varieties based on drug safety considerations, which, while mitigating medication risks, also results in the waste of medicinal resources. Existing methods such as processing and combination therapy also have limitations in reducing the toxicity of these herbs, including limited efficacy and difficulties in standardizing processes, making it challenging to balance toxicity control with the preservation of pharmacological effects. Based on this, this paper systematically reviews the deletion of herbal materials and proprietary Chinese medicine formulations from the last five editions of the Chinese Pharmacopoeia, summarizing the medicinal value and controversies surrounding herbs derived from the Aristolochia genus, the toxic mechanisms of aristolochic acid, and existing detoxification methods along with their limitations. Addressing these limitations, this paper proposes application strategies for gene editing, enzyme engineering, and fermentation engineering in reducing the toxicity of Aristolochia and other Chinese medicinal herbs, from the perspective of modern biotechnology, and explores new pathways for the precise regulation of the synthesis and degradation of toxic components. Compared with traditional detoxification methods, the use of modern biotechnology holds promise for precisely regulating the synthesis or degradation of toxic components, thereby reducing toxicity while preserving the overall therapeutic efficacy of the herbal materials, with the aim of achieving "detoxification while preserving efficacy". Future efforts should be intensified to verify the botanical sources of toxic Chinese herbal medicines, elucidate the biosynthetic pathways of toxic components, and investigate their toxic mechanisms. Additionally, the development and utilization of toxic Chinese herbal resources should be advanced to promote the high-quality development of traditional Chinese medicine through inheritance, innovation, modernization, and internationalization.

Key words

aristolochic acid / toxic Chinese medicine / Caulis Aristolochiae Manshuriensis / biotechnology / toxicity reduction

引用本文

荣千漪, 濮春娟, 李琦爽, 郑汉, 王嘉成, 吴啟南. 现代生物技术在马兜铃等有毒中药中的应用前景刍议. 药学学报, 2026 , 61 (8) : 2914 -2929 . DOI: 10.16438/j.0513-4870.2026-0261

Qian-yi RONG, Chun-juan PU, Qi-shuang LI, Han ZHENG, Jia-cheng WANG, Qi-nan WU. A preliminary discussion on the application prospects of modern biotechnology in toxic Chinese medicines including Aristolochia[J]. Acta Pharmaceutica Sinica, 2026 , 61 (8) : 2914 -2929 . DOI: 10.16438/j.0513-4870.2026-0261

正文

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中医药作为中华民族传承千年的瑰宝, 其临床疗效已经过长期临床实践的验证, 具有独特的优势与价值。然而, 中药安全性不仅是中医临床的底线要求, 更是推动中医药实现现代化、走向国际化的前提。近年来, 有毒中药引发的药害事件屡见报道^{[1, 2]}, 引发了社会对中药安全性的广泛关注与高度担忧。

以含马兜铃酸类成分的中药为例, 1993年, 比利时学者Vanherweghem首次报道了含广防己的中药减肥药与快速进展性间质性肾炎之间的关联^{[3, 4]}。随后, 全球范围内报道了多例因服用含马兜铃酸中药导致不可逆肾衰竭和尿路上皮癌的病例^{[5, 6]}。这些安全性事件使此类中药的临床应用备受争议。为保障患者用药安全, 近5版的中国药典持续调整收录品种, 先后剔除了关木通、广防己等含马兜铃酸的有毒中药。这种直接禁用或删减品种的举措, 虽然在临床层面有效阻断了毒性暴露风险, 但也极大地限制了相关中药潜在药用价值的深度挖掘, 导致部分具有独特临床疗效的传统医药资源难以被继续开发与合理利用。

当前, 围绕该类中药减毒的研究已涉及炮制、配伍、微生物发酵等多种方法, 但多聚焦于毒性成分的后处理或外源干预, 难以实现减毒与存效的精准平衡。因此, 探索安全、可控、精准、高效的新型减毒方法极为迫切。

现代生物技术在中药资源品种培育、活性成分调控与品质改良等领域已展现出良好应用潜力, 为解决传统减毒技术的不足提供了新的可能。本文对减毒的研究进展、马兜铃酸的致毒机制及其生物合成途径进行综述, 针对现有减毒技术的不足探索优化方式, 提出以现代生物技术为核心的减毒新思路, 从马兜铃酸生物合成途径出发, 通过基因编辑、酶工程、细胞工程、发酵工程等手段, 靶向调控毒性成分合成通路中的关键酶基因与调控节点, 实现毒性成分的源头精准减量, 同时保留药材中其他类型的有效成分。该思路将减毒研究的重心由外源干预转向内源合成途径调控, 为实现有毒中药的毒性控制与临床药效的协同保障提供了新路径。

1　近五版的中国药典对有毒中药的收载情况概述

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从2005年至2025年, 中国药典历经五次更新修订, 在这五版药典中, 对于关木通、广防己、青木香、马兜铃和天仙藤共5种明确具有肝肾毒性的有毒中药不再予以收载, 并将细辛药用部位由“全草”修订为“根及根茎”。上述品种的删减与药用部位的修订, 其根本原因在于相关药材中含有马兜铃酸。下面结合各版药典的关键修订节点, 梳理其脉络, 详见表1^[7-18]。

2　含马兜铃酸有毒中药的药用价值与争议

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2.1　传统药用价值

在中医药长期发展历程中, 上述5种含马兜铃酸的有毒中药在传统临床实践中用于治疗多种病症。在历代古籍中, 马兜铃、青木香、天仙藤、细辛这四种药材均有明确记载, 且具有较高的药用价值与地位, 其药用部位、性味归经及功效应用各有侧重。

马兜铃是马兜铃科植物北马兜铃(Aristolochia contorta Bge.) 或马兜铃(Aristolochia debilis Sieb.et Zucc.) 的干燥成熟果实。《本草备要》^[19]载其“体轻而虚……寒能清肺热, 苦辛能降肺气……治痰喘促, 血痔漏疮, 大肠经热”, 而《本草求真》^[20]亦言其“入肺, 清热, 降气, 除寒……肺热痰喘声音不清者, 服此最宜。且其体轻则性上涌, 故纂要治蛇虫毒。一味汤煎, 服之探吐, 其毒即解”。故其具有清肺降气、止咳平喘、清肠消痔之功能, 可用于肺热咳喘、痰中带血、肠热痔血、痔疮肿痛、蛇虫咬伤等症的治疗。

青木香是马兜铃科植物马兜铃(A. debilis Sieb. et Zucc.) 的干燥根。《神农本草经》^[21]记载其“味辛, 温。主治邪气, 辟毒疫温鬼, 强志, 治淋露。久服不梦寤魇寐”, 《本草求真》^[22]则称其“味辛而苦, 微寒无毒, 可升可降, 可吐可利。散毒、泄热。凡人感受恶毒而致胸膈不快, 则可用此上吐, 以其气辛而上达也。感受风湿而见阴气上逆, 则可用此下降, 以其苦能泄热也”。由此可知, 青木香具有平肝止痛、解毒消肿之功能, 可用于眩晕头痛, 胸腹胀痛, 痈肿疔疮, 蛇虫咬伤等症的治疗。

天仙藤为马兜铃科植物马兜铃(A. debilis Sieb. et Zucc.) 或北马兜铃(A. contorta Bge.) 的干燥地上部分。在《本草求真》^[23]中记载其“味苦, 气温。活血, 利水……水无不利, 风无不除, 血无不通, 痛与肿均无不治……止属妊娠子肿, 及腹痛风痹等症”。据此, 天仙藤具有行气活血, 利水消肿之功能, 可用于脘腹刺痛, 关节痹痛, 妊娠水肿等症的治疗。

细辛是马兜铃科植物北细辛[Asarum heterotropoides Fr. Schmidt var. mandshuricum (Maxim.) Kitag.]、汉城细辛(Asarum sieboldii Miq. var. seoulense Nakai) 或华细辛(Asarum sieboldii Miq.) 的干燥全草。在《神农本草经》^[24]《本草经集注》^[25]《新修本草》^[26]《本草备要》^[27]中均载其“味辛温, 无毒。主治咳逆……死肌。温中, 下气, 破痰, 利水道, 开胸中, 除喉痹, 齆鼻, 风痫、癫疾, 下乳结, 汗不出, 血不行, 安五脏, 益肝胆, 通精气。久服明目, 利九窍, 轻身, 长年”, 另有《本草蒙筌》^[28]言其“味大辛, 气温。气厚于味, 升也, 阳也……止本经头痛如神, 治诸风湿痹立效……口臭及选齿肿疼, 煮浓汁含”。在《本草纲目》^[29]中记载道“甄权: 添胆气, 治嗽, 去皮风湿痒, 风眼泪下, 除齿痛, 血闭, 妇人血沥腰痛。好古: 润肝燥, 治督脉为病, 脊强而蹶。时珍: 治口舌生疮, 大便燥结, 起目中倒睫”, 《本草求真》^[30]中亦载“水停心下, 口吐涎沫, 宜辛以润之。耳聋鼻衄、倒睫便涩者, 并宜用此调治”。由上述可知, 细辛具有解表散寒, 祛风止痛, 通窍, 温肺化饮之功能, 可用于治疗风寒感冒, 头痛, 牙痛, 鼻塞流涕, 鼻鼽, 鼻渊, 风湿痹痛, 痰饮喘咳等病症。

与上述四种药材不同, 关木通与广防己在清代及以前的本草古籍中并无药用记载, 二者属于近现代以来因药源不足或基原混淆而产生的误用品种。关木通是马兜铃科植物东北马兜铃(Aristolochia manshuriensis Kom.) 的干燥藤茎, 其作为药材使用的记载始于近代。近现代因东北等北方地区药源不足, 又因关木通的藤茎“有细细孔, 两头皆通”的形态特征与传统木通相似, 同时具备一定利水功效, 被就地取材作传统木通科木通(Akebia quinata) 用^[31-33]。广防己是马兜铃科植物广防己(Aristolochia fangchi Y. C. Wu ex L. D. Chou et S. M. Hwang) 的干燥根。清代及以前防己主流基原为马兜铃科异叶马兜铃(Aristolochia heterophylla) (汉中防己) 及防己科木防己(Cocculus orbiculatus), 明代后粉防己(Stephania tetrandra) 逐步成为主要基原, 而广防己入药始于民国时期, 因当时未认识到其含马兜铃酸类毒性成分, 在广东地区被当作防己使用并广销其他地区^[34]。

2.2　现代药理研究

马兜铃、青木香、天仙藤、细辛这四种药材在历代本草古籍中早有药用记载, 现代药理研究进一步证实, 马兜铃属中药具有丰富且多样的药用潜力。

综合现有关于马兜铃科马兜铃属中药化学及生物活性的研究文献可知, 我们总结可知该属植物的活性成分以次生代谢产物为主, 主要化学成分有马兜铃酸类、木脂素类、萜类、酚类化合物等, 具有抗癌、抗菌、抗寄生虫、抗炎、抗风湿、抗氧化、抗蛇毒、神经保护、抗纤维化、抗糖尿病等多种生物活性^[35-39]。

关木通虽不是传统古籍中木通的正品来源, 其现代药理研究同样取得了诸多进展。关木通中的主要化学成分为马兜铃酸类、马兜铃苷、马兜铃酰胺、马兜铃内酰胺以及生物碱, 如木兰花碱、满洲防己碱、四氢防己碱和马兜铃吡啶酮。其中, 马兜铃内酰胺类化合物具有抗肿瘤潜力, 而马兜铃酰胺Ⅱ能发挥抗炎作用。木兰花碱不仅具有治疗糖尿病、抗炎、神经精神调节、免疫调节、降血压、抗氧化及抗真菌等作用, 其抗癌活性也已得到证实, 对脑肿瘤、胃癌、乳腺癌、肺癌以及肝细胞癌等细胞系都具有细胞毒性^[40]。另有研究表明, 关木通具有保护非酒精性脂肪性肝炎(NASH) 的作用, 在高脂饮食诱导的小鼠NASH模型中, 关木通乙酸乙酯提取物(2.5 mg·kg^-1·d^-1) 可改善肝脏病理、调节血脂与肝功能、增强抗氧化能力、调控脂质代谢、氧化和炎症相关基因与有丝分裂原活化蛋白激酶(mitogen-activated protein kinases, MAPKs) 信号通路, 且该剂量下未观察到肾毒性或致癌性^[41]。除上述药理活性外, 关木通在生物合成领域也展现出应用潜力, 关木通愈伤组织和毛状根的水提取物可作为还原剂和稳定剂, 用于功能性银纳米粒子的生物合成, 且所制备的纳米银离子具有抗菌活性和抗癌潜力^[42]。

2.3　关于含有马兜铃酸的有毒中药的争议

目前, 含马兜铃酸中药的肾毒性已得到明确证实, 其引发的马兜铃酸肾病(aristolochic acid nephropathy, AAN) 已成为明确的药源性疾病。Wang等^[43]在对近十年165例含马兜铃酸中药不良反应或事件的研究中发现, 大多数反应为肾损害, 且此类肾损伤具有不可逆性, 主要与超剂量应用或小剂量长期累积应用有关。

此外, 马兜铃酸的致突变性也已得到大量研究证实。国际癌症研究机构^[44]和世界卫生组织^[45]先后于2002、2012年将马兜铃酸列为一级致癌物, 美国、英国等多个国家或地区禁止销售和使用含马兜铃酸类成分的中草药^[46]。此外, 欧盟将其认定为不可接受的健康风险, 通过统一法规与药物警戒实现全欧盟严格管控, 并全面禁用含马兜铃酸的中药, 不允许以任何草药药品形式上市。该类中草药无法通过欧盟任何注册审批路径, 同时被要求严格原料鉴定、禁止掺伪并列为必检禁用成分^[47]。现有诸多研究均表明, 含马兜铃酸的草药与癌症发生风险存在相关性^[48-50]。但也有研究者对马兜铃酸与肝癌相关性质疑, 认为二者存在直接关联的证据尚不充分^[51]。

马兜铃属植物具有悠久药用历史, 多个品种在传统中医理论与临床应用中占据重要地位, 部分含马兜铃酸中药在特定病症治疗中展现出不可替代的疗效。尽管目前已有部分含马兜铃酸的中药材被替代, 但替代药材在药效匹配度上仍存在争议。诸多学者认为替代药材缺乏坚实的临床疗效基础, 且在功效上无法完全等效^[52]。

综上, 含马兜铃酸中药的毒性风险与药用价值之争客观存在, 因此探索并建立兼顾临床药效与毒性成分精准控制的技术方法, 对于该类中药的安全合理应用与传承创新发展具有重要意义。

3　马兜铃酸的致毒机制

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3.1　毒性成分

马兜铃酸类物质属于硝基菲羧酸类化合物, 在马兜铃属、细辛属等马兜铃科植物中广泛存在。这类物质主要分为两大类别, 分别是马兜铃酸(aristolochic acids, AAs) 和马兜铃内酰胺(aristolactams, ALs)。其中, 马兜铃内酰胺的来源有两种: 一是部分植物本身就含有该物质; 二是马兜铃酸在动物体内经过硝基还原酶的还原作用后产生的代谢产物。在大多数马兜铃属植物中, 马兜铃酸的含量要高于马兜铃内酰胺^[53]。马兜铃内酰胺的毒性也备受关注, 在实验条件下未观察到明显的肾脏和肝脏毒性, 但其体外实验有明显的细胞毒性^[54]。马兜铃酸包含A~D等多种类型, 其中, 马兜铃酸A又称马兜铃酸I (AA-I), 其毒性最强, 马兜铃酸B又称马兜铃酸Ⅱ (AA-Ⅱ), 毒性仅次于马兜铃酸A, 且二者共存时可增强毒性。此外, 马兜铃酸Ⅰa有微弱基因毒性, 马兜铃酸Ⅳ具有弱致突变性, 而马兜铃酸C、D在部分实验条件下未观察到明显肝肾毒性^{[55, 56]}。马兜铃酸及其衍生物的化学式见图1。

3.2　致毒机制

马兜铃酸类物质的毒性作用机制主要有五个方面。其一, DNA损伤与基因突变, 其经代谢生成活性中间体, 形成DNA加合物引发TP53基因异位突变, 高浓度下也可直接诱导基因突变^[57-59]。其二, 细胞直接损伤与凋亡调控, 大剂量致肾小管上皮细胞坏死, 长期小剂量引发肾间质纤维化, 且呈浓度依赖性诱导细胞凋亡^[60-62]。其三, 诱发氧化应激, 增加活性氧簇和氮类生成, 破坏氧化-抗氧化平衡^{[63, 64]}, 还可诱导内质网应激^[65]。其四, 调控多条信号通路, 涉及肾脏纤维化、细胞凋亡、炎症反应及肝癌相关通路, 推动损伤与癌变^[66-68]。其五, 通过miRNA差异表达, 在翻译水平抑制靶基因表达, 介导肾损伤^[69]。这些机制相互关联、共同介导了马兜铃酸类物质的毒性效应, 具体机制见图2^[57-69]。

此外, 含马兜铃酸的有毒中药与其他药物联用时或可产生协同效应。环孢素A可增强MPP+ (N-甲基-4-苯基吡啶离子, N-methyl-4-phenylpyridinium ion) 诱导的SH-SY5Y细胞凋亡, 而马兜铃酸则抑制该凋亡, 提示二者通过不同机制影响细胞凋亡, 联用时可能产生复杂的相互作用, 但具体作用机制尚不明确^[70]。另有研究发现, 泼尼松(prednisone) 对急性马兜铃酸肾病具有肾保护作用, 且与发酵虫草菌粉联用效果更佳^[71]。鉴于上述协同效应的研究发现, 临床用药需更加谨慎, 且需加强对具体机制的深入探究。

4　现有减毒方法及其局限性

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4.1　炮制减毒

马兜铃科中药因含马兜铃酸类物质而具有毒性, 炮制减毒是保障其临床用药安全的重要手段。传统炮制方法多样, 涵盖炒、炙、煮等, 核心通过改变毒性成分含量或结构以达减毒目的。Liu等^[72]发现炒制和蜜炙均降低马兜铃中马兜铃酸A的含量, 其中蜜炙效果优于炒制, 可降低51.77%, 但该研究未对炮制后药效成分变化进行检测。Zhang等^[73]发现在醋炙、蜜炙、姜炙、碱制、盐炙法中, 蜜炙法是关木通减毒存效的最佳炮制方法。上述5种炮制方法对有效成分齐墩果酸和常春藤皂苷元也均有不同程度的影响, 其中蜜炙法对两者影响较小, 与生品相比无显著差异。其后, Lai等^[74]采用仿生炮制青木香, 用猪肝匀浆温孵体系进行减毒和转化, 其马兜铃酸A含量去除率可达92.1%并同时伴随马兜铃酸类似物的转化, 而药材中其他成分含量无明显变化。Yang等^[75]对比研究7种炮制方法, 发现均能降低马兜铃中马兜铃酸含量, 其中, 碱制-醋制法下降最多, 达到50.54%, 但同样未考察炮制后的药效变化。Wang等^[76]提及碱制与醋炙结合虽能有效地去除马兜铃酸, 但需使用碳酸氢钠等弱碱性溶液并严格控制温度。

现有炮制方法在马兜铃科植物减毒方面仍存在局限, 尽管多种炮制方法能不同程度降低毒性成分含量, 但降幅有限, 且不同方法的减毒幅度差异较大。更为关键的是, 当前相关研究对炮制减毒后的整体药效变化考察不足, 即便部分炮制方法对已知有效成分含量影响较小, 也不足以直接说明药材整体药效未发生改变。此外, 效果较好的碱制与醋炙结合法还需严格控制条件, 导致炮制工艺难以统一标准化, 给实际应用带来不便。

4.2　配伍减毒

中药配伍减毒在含马兜铃酸类中药的安全应用中同样具有重要意义, 其形式主要包括单味药配伍与复方中药配伍, 两者通过不同的配伍方式均能在一定程度上减轻马兜铃酸类物质的毒性, 但也存在诸多问题。

4.2.1　单味药配伍

Zhu等^[77]在综述单味中药与含马兜铃酸的中药配伍后对肾脏的减毒作用实验研究进展时指出, 具有减毒作用的单味中药有四类, 分别为: 补益(黄芪、冬虫夏草、甘草、当归)、活血(牡丹皮、丹参)、清热(生地黄、竹叶、黄连)、泻下(大黄)。Liu等^[78]研究了马兜铃与当归、甘草、射干、半夏的配伍效果。结果显示, 当归与马兜铃配伍以2∶1比例配伍时, 降低马兜铃酸A的含量达67.63%, 而甘草配伍反而增加了马兜铃酸A的含量。Ma等^[79]发现关木通与黄连配伍比例为1∶1.5时, 马兜铃酸A含量下降最为明显, 达72%。Shao等^[80]发现关木通与干姜以1∶2的比例配伍使用时, 关木通中马兜铃酸A含量降低率最高, 达到87.79%, 且配伍减毒后该药材对大鼠利尿作用没有明显改变。

4.2.2　复方中药配伍

Ding等^[81]比较单味关木通及其复方龙胆泻肝丸、导赤散对大鼠的肾毒性, 发现龙胆泻肝丸与导赤散对大鼠造成的肾脏损害较单味关木通为轻, 表明复方配伍能够减轻关木通肾毒性。Mao等^[82]发现关木通与脑灵片共煎后, 马兜铃酸A的含量明显降低, 降低率达49.73%。此外, 六味地黄丸与广防己共煎后可显著降低广防己中马兜铃酸A的含量。而Sun等^[83]发现滋阴补肾丸与广防己或关木通共煎后均可降低其中的马兜铃酸A含量。上述研究均未对炮制后药效是否变化进行检测。

尽管通过配伍可使马兜铃酸A的含量得到一定程度的下降, 但其残留量仍处于较高水平且对于配伍降低马兜铃总酸含量变化的研究较少。同时, 大多数研究未对配伍后的药效变化进行系统评价, 即便开展药效检测, 也仅局限于药材单一药理作用的考察, 缺乏对整体药效的综合评估。此外, 配伍过程中, 由于配伍比例的精准性控制不足, 煎煮方式不同, 以及同种药材因产地、采收时间、加工方式等因素导致的质量差异, 也可能造成减毒效果的不稳定性。

4.3　其他减毒方法

除传统炮制与配伍减毒方法外, 当前已发展出多种新型减毒办法。

4.3.1　微生物发酵技术

Cao等^[84]选取黑曲霉、米曲霉等10个菌种, 以关木通、青木香、马兜铃和寻骨风药材粉末为原料, 运用液体发酵技术进行生物转化脱毒。结果表明, 枯草芽孢杆菌对这4种中药材中的马兜铃酸A都有一定的转化作用, 但降低幅度最大不超过50%。发酵减毒后药材中其他化学成分出现一定增减, 但未明确具体变化成分。Liu等^[85]探讨真菌发酵对广防己中马兜铃酸A含量的影响, 结果显示, 两种发酵品GF1和GF2中马兜铃酸A的含量下降率分别为68.67%和52.67%, 并发现广防己发酵炮制后同样出现成分增减变化, 但其具体成分亦未明确。

4.3.2　现代分离纯化技术

① 分子印迹法: Xiao^[86]采用可逆加成断裂链转移聚合(RAFT) 法制备了马兜铃酸分子印迹微球, 所得分子印迹聚合物(MIP) 对模板马兜铃酸A具有良好的特异性和选择性吸附能力, 可至少重复使用6次。取25.0 mg MIP吸附5.0 mL关木通乙醇提取物(马兜铃酸A质量浓度为0.001 8 mg·mL^-1), 结果马兜铃酸A含量降至液相色谱的检测限(6.47 ng·mL^-1) 以下, 表明MIP可用于去除天然产物中的马兜铃酸A, 但该研究未考察其对药效的影响。②吸附法: Sun等^[87]采用离子交换法从中药材北细辛中获得无毒提取物的制备工艺, 可去除北细辛药材中具有挥发性的黄樟醚, 以及非挥发性的马兜铃酸、乌头碱、去甲乌头碱等有毒成分, 并较好地保留有效成分, 但未通过实验对有效成分的保留效果进行验证。

4.3.3　分子生物技术

Hui^[88]通过转录组测序分析北细辛根和叶的差异基因, 筛选出9个天冬氨酸氨基转移酶相关unigene, 以c211451_g1_i2为候选基因(Ah AST), 克隆其全长cDNA, 构建原核和植物过表达载体, 初步实现该基因在北细辛愈伤组织中的转化, 为从基因层面控制马兜铃酸合成提供了思路, 但该研究未对编辑后药材药效的变化进行检测。

4.3.4　天然产物及活性成分介入减毒

各类天然产物及活性成分可在机体内部多靶点减轻马兜铃酸造成的靶器官毒性损伤。①五味子油: 通过调节上游代谢酶来减少马兜铃酸有毒代谢产物的产生, 并直接抑制下游的细胞凋亡和氧化应激相关损伤, 缓解马兜铃酸A引起的体内外肾毒性^[89]; ②姜黄素: 通过激活SIRT1/Nrf2/HO-1信号通路, 减轻马兜铃酸A诱导的肾损伤^[90]; ③巴马汀: 通过上调IKBKB激活EGFR通路, 恢复马兜铃酸损伤心脏的形态与血供, 减轻心脏毒性^[91]; ④小檗碱: 与马兜铃酸自组装形成异质线性超分子(A-B), 显著降低马兜铃酸毒性, 减轻急性肾损伤^[92]; ⑤黄芩苷: 通过芳香烃受体诱导CYP1A, 降低马兜铃酸A处理小鼠的血尿素氮、肌酐水平, 减轻肾损伤^[93]; ⑥冬虫夏草: 有效地拮抗马兜铃酸诱导的组织纤维化, 可能与抑制TGF-β1和Snail的表达有关^[94]; ⑦黄芩素Ⅱ (skullcapflavone Ⅱ, SFII) : SFII通过抑制细胞质NAD(P)H醌氧化还原酶1 (NQO1) 活性, 在体内外均能缓解马兜铃酸A诱导的DNA损伤和肝肾毒性, 且无明显不良反应^[95]。上述研究均未对减毒后药效是否变化进行研究。

4.3.5　维生素及营养物质介入减毒

此类方法主要通过补充特定的外源性抗氧化剂或代谢调节剂, 在机体内部改善由马兜铃酸引发的氧化应激与代谢紊乱, 从而避免靶器官受损。①维生素C: 通过降低氧化应激介导的细胞死亡途径, 减少马兜铃酸诱导的肾小管细胞H₂O₂水平、Caspase-3活性及细胞毒性, 从而减轻马兜铃酸对肾小管细胞的毒性^[96]; ② BT2 (3, 6-二氯苯并噻吩-2-羧酸, 3, 6-dichlorobenzothiophene-2-carboxylic acid): 激活支链氨基酸分解代谢, 减少支链氨基酸积累、抑制mTORC1信号通路, 并改善线粒体生物能量学, 从而保护肾功能、减轻肾小管损伤和炎症^[97]。上述研究均未对减毒后药效是否变化进行研究。

4.3.6　信号通路调节及分子靶点干预减毒

针对马兜铃酸已知的致毒机制, 通过特异性激活或抑制相关的下游信号通路及核心分子靶点, 能够在组织与细胞层面有效阻断其介导的炎症及凋亡级联反应。①酪氨酸激酶活性选择性抑制剂fms-I: 证实巨噬细胞是慢性马兜铃酸肾病中导致进行性肾小管间质损伤的关键炎症细胞, 通过使用fms-I抑制巨噬细胞积累成功改善肾功能, 为慢性马兜铃酸肾病减毒提供新方向^[98]; ②松弛素: 通过激活PI3K/Akt信号通路, 减轻马兜铃酸诱导的人肾小管上皮细胞凋亡^[99]; ③ Smad7: Smad7过表达可抑制TGF-β/Smad3和NF-κB信号通路, 从而减缓慢性马兜铃酸肾病进展, 为治疗提供新靶点^[100]; ④雷帕霉素: 通过抑制雷帕霉素靶蛋白(mTOR) 及其下游靶点S6K1的磷酸化, 从而促进了肾脏细胞自噬并减少了细胞凋亡^[101]; ⑤双香豆素: 通过抑制肾NQO1活性, 减少马兜铃酸A的硝基还原, 降低其代谢产物肾毒性^[102]; ⑥ miR-766-3p和miR-671-5p: 直接靶向关键生物活化酶NQO1, 下调其表达, 减轻马兜铃酸诱导的肝细胞毒性与氧化应激, 减弱肝毒性^[103]。上述研究均未对减毒后药效是否变化进行研究。

尽管学界已针对马兜铃酸的减毒策略开展了大量探索, 提出了包括天然产物干预、信号通路调控、分子靶点干预等多种技术路径, 但现有研究成果仍存在明显局限。其一, 尚无能够完全消除其毒性的方案, 多数方法仅能在一定程度上降低毒性强度。其二, 部分减毒手段在削弱毒性的同时, 易对含马兜铃酸类药材中除马兜铃酸外的其他药效成分产生非特异性抑制。此外, 中药素有“毒为药用”的特点, 毒性成分与药效成分常共存于同一化学成分, 加之马兜铃酸本身药效机制复杂且尚未完全阐明, 在降低或消除毒性的过程中, 其临床疗效亦可能随之减弱或发生改变。目前既缺乏毒性降低与药效保留兼顾的理想方案, 也缺少科学的药效保留评价体系。其三, 少数具有潜力的减毒策略因操作流程复杂、成本较高或依赖特殊实验条件, 缺乏向实际应用场景转化的可行性。因此, 当前马兜铃酸减毒研究仍面临许多困难。

5　现代生物技术在马兜铃等有毒中药中的应用前景

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5.1　马兜铃酸的生物合成途径

马兜铃酸A是一种硝基菲羧酸衍生物, 早期的同位素示踪实验表明其生物合成属于苄基异喹啉生物碱(benzylisoquinoline alkaloids, BIAs) 代谢网络的特殊分支^[104]。近年来, 结合多组学分析和越来越多的生物化学实验逐步绘制出其基本的代谢途径轮廓, 见图3^[105-110]。马兜铃酸与BIA一样, 其生源途径起源于L-酪氨酸(L-tyrosine), 经历1-BIA骨架形成、结构修饰及阿朴菲骨架形成等步骤, 再通过下游多步氧化还原反应和后修饰最终形成马兜铃酸。

具体来看, 马兜铃酸生物合成的起始阶段由酪氨酸脱羧酶(tyrosine decarboxylase, TYDC) 催化L-酪氨酸生成酪胺(tyramine), 再由酪氨酸3-羟化酶(tyrosine 3-hydroxylase, 3OHase) 催化酪胺生成多巴胺(dopamine); 同时, L-酪氨酸也可以在酪氨酸转氨酶(tyrosine aminotransferase, TyrAT) 和4-羟基苯乙醛脱羧酶(4-hydroxyphenylacetaldehyde decarboxylase, 4HPPDC) 的连续催化下生成4-羟基苯乙醛(4-hydroxyphenylacetaldehyde, 4HPAA)^[105]。多巴胺和4-HPAA在去甲乌药碱合成酶(norcoclaurine synthase, NCS) 的催化下发生Pictet-Spengler反应生成第一个BIA骨架中间体(S)-去甲乌药碱(S-norcoclaurine)^[106]。(S)-去甲乌药碱继续在两个甲基转移酶和一个CYP的催化生成3′-羟基-N-甲基乌药碱(3′-hydroxy-N-methylcoclaurine) ^[107]。根据之前同位素示踪的实验报道, 马兜铃科植物中存在一个未知的C3′位羟基甲基转移酶将3′-羟基-N-甲基乌药碱转化为东罂粟灵(orientaline), 该化合物是马兜铃酸生物合成的关键前体^{[104, 105]}。另一方面, 植物中还存在另一条通往东罂粟灵的代谢途径, 即L-酪氨酸可以在酪氨酸羟化酶(tyrosine hydroxylase, TH) 和DHPAAS的催化下生成3, 4-二羟基苯乙醛(3, 4-dihydroxyphenylacetaldehyde, 3, 4-HPAA), 该中间体也可以在NCS的作用下与多巴胺发生PS反应生成去甲劳丹碱(S-norlaudanosoline), 进一步通过6OMT、CNMT及未知的3′OMT的甲基化作用生成东罂粟灵^{[108, 109]}。

随着东罂粟灵的形成, 代谢流进入阿朴菲骨架形成阶段。东罂粟灵在潜在的CYP催化下发生C-C苯酚偶联反应, 生成原阿朴菲骨架的中间体orientalinone。然而已知的催化原阿朴菲骨架形成的CYP80Q亚家族CYP仅被报道可以催化乌药碱和N-甲基乌药碱生成相应的原阿朴菲骨架产物crotsparine和glaziovine, 并未测试其是否可以催化东罂粟灵生成相应产物。接着, orientalinone还原为orientalinol, 再经过二烯醇-苯酚重排、亚甲基二氧桥形成和氧化裂解等多酶参与的复杂反应最终形成马兜铃酸, 而催化这一系列反应的关键酶尚未被发现^{[107, 110]}。

5.2　现代生物技术在马兜铃属有毒中药中的应用策略

通过对马兜铃酸生物合成途径的系统解析, 明确了其以L-酪氨酸为起点, 经苄基异喹啉生物碱骨架构建、关键前体东罂粟灵生成及阿朴菲骨架环化等步骤最终形成的完整路径, 同时定位了TYDC、NCS等关键合成酶与核心调控节点。这些关键靶点与分子机制的阐明, 为毒性成分的靶向干预提供了理论基础与作用位点, 是开展减毒研究的前提。

基于上述合成途径, 可综合运用基因编辑、细胞工程、酶工程及发酵工程等现代生物技术, 实现马兜铃酸合成抑制或定向降解, 为有毒中药减毒增效提供可行技术路径(图4^[111-125])。

5.2.1　基因编辑技术

基因编辑是利用分子生物学技术, 对基因组中的DNA序列进行修饰的技术, 能够对中药材基因组进行精确修饰, 实现毒性成分的源头控制^[111]。其中, CRISPR-Cas系统因操作简便、编辑效率高等特点, 成为应用最广泛的基因编辑工具, 其利用RNA引导的核酸酶对DNA或RNA进行位点特异性识别和切割, 通过同源重组实现基因敲入、精确点突变或片段替换^{[112, 113]}。此外, 碱基编辑技术结合Cas9切口酶(nCas9) 和脱氨酶, 可实现单碱基转换^[112]; 引导编辑技术结合nCas9和逆转录酶, 并使用引导编辑gRNA (pegRNA), 可实现包括点突变、小片段插入和缺失在内的各种类型的精确基因编辑^[114]。

这一技术主要通过两种方式实现马兜铃属有毒中药减毒存效, 一是直接编辑毒性成分合成通路上的基因, 二是靶向编辑调控合成通路的转录因子。由AAs生物合成途径可知, 其上游合成途径中的TYDC、4HPPDC、NCS等酶直接参与马兜铃酸骨架合成, 可通过组学测序技术, 获得上述酶基因的全长序列, 再利用CRISPR/Cas9技术, 设计特异性gRNA靶向上述酶基因位点, 以此实现基因敲除。例如, 敲除4HPPDC酶基因可阻断酪氨酸转化为4-羟基苯乙醛, 进而抑制骨架中间体(S)-去甲乌药碱产生及后续马兜铃酸的合成。此法虽有望实现马兜铃酸“零合成”, 但完全敲除基因有导致植物代谢紊乱风险。因此, 可引入碱基编辑技术, 对关键基因的编码区或启动子区进行单碱基替换, 改变酶的结构与活性, 降低其催化效率, 使前体物质如L-酪氨酸等不再流向马兜铃酸的合成, 而是转向有利于临床药效的木脂素类、生物碱类等次生代谢产物合成路径中。此外, 通过编辑调控该合成通路的核心转录因子, 可同步实现通路上多个功能基因的协同下调表达, 从上游调控层面高效抑制毒性成分的整体合成效率, 达到马兜铃酸合成量下降的目标。这种方式相比单基因编辑更具高效性。该技术在丹参(Salvia miltiorrhiza Bunge)、人参(Panax ginseng C. A. Mey)、三七[Panax notoginseng (Burk.) F. H. Chen] 等药用植物中已得到成功应用, 通过编辑药用成分合成相关基因或其调控转录因子, 提高其药用成分含量^{[115, 116]}, 为马兜铃属有毒中药减毒研究提供借鉴。

5.2.2　细胞工程技术

细胞工程是利用细胞生物学与分子生物学技术, 对细胞整体或细胞器进行定向操作与调控的技术, 该技术可突破传统中药材种植受环境制约大、周期长及成分波动大的局限^[117]。在马兜铃属植物的减毒存效应用中, 重点在于建立悬浮细胞培养和毛状根培养体系。通过构建马兜铃、关木通等药用植物的反应器培养体系, 可以通过人工精确施加诱导子, 例如特定波长的光照、茉莉酸甲酯(MeJA)、真菌多糖等非生物或生物信号分子等, 特异性地抑制毒性成分马兜铃酸的表达, 同时激活有效药用成分的合成基因^[118]。此外, 现有研究已成功建立了关木通的毛状根培养体系, 发现毛状根中马兜铃酸的含量明显低于完整植株, 且其药用成分花木兰碱含量增多^{[40, 119]}。因此, 毛状根培养技术在马兜铃属植物减毒中展示出优势。

5.2.3　酶工程技术

酶工程是利用分子生物学、蛋白质工程等技术, 对酶的基因序列或酶分子本身进行修饰与改造的技术^[120]。其中, 酶分子改造技术为开发高效、特异的马兜铃酸降解酶提供了新途径^[121]。现有研究推测O-去甲基化酶(O-demethylase, ODM) 是马兜铃酸A降解的关键候选酶^[122]。因此, 或可利用AI辅助的蛋白质结构预测与分子对接技术解析其与马兜铃酸结合的具体靶点, 并基于此运用定向进化与理性设计, 对酶的氨基酸序列进行突变改造, 提高其在药物中的稳定性、催化效率与底物特异性。最终构建出高效降解有毒成分的酶反应体系, 以此特异性地将马兜铃酸A降解为无毒小分子, 并保留原有药材的其他活性物质。

5.2.4　发酵工程技术

发酵工程是利用微生物学、生物化学技术, 对微生物的代谢过程或发酵条件进行调控与优化的技术^[123]。现有研究已从不同环境中筛选出多种能够降解马兜铃酸的微生物, 为马兜铃属植物的生物减毒提供了丰富的菌种资源。内生真菌的筛选与鉴定是微生物减毒研究的重要方向, Wang等^[122]从细辛中分离得到一株能够降解马兜铃酸A的内生真菌新宇宙孢菌(Neocosmospora solani), Xiang^[124]从马兜铃根际土壤中获得33株纯培养菌株, 其中11株对马兜铃酸A具有降解能力, 降解能力最强的菌株被鉴定为鞘氨醇单胞菌属(Sphingobium sp.)。药用真菌双向性固体发酵工程在雷公藤减毒研究中成功应用, 也为马兜铃属有毒中药减毒研究提供了参考^[125]。但上述方法依赖于自然筛选的单一菌株, 降解效率有限。未来需进一步优化工业化发酵条件提升减毒效果, 同时可以尝试构建合成微生物群落, 通过将高效马兜铃酸降解酶的基因导入到细胞中, 构建工程化的高效降解菌株。

5.3　“减毒存效”的系统评价与验证体系刍议

在含马兜铃酸类有毒中药的减毒研究中, 减毒后药效保留的评价与验证是至关重要的。然而, 当前多数研究对减毒后药效变化的验证相对薄弱, 尚缺乏系统、科学的综合评价验证体系。鉴于传统中药通过多成分、多靶点、多途径协同发挥整体疗效, 评价现代生物技术干预后的中药是否真正实现“存效”, 不能仅局限于单一或少数指标成分的保留率, 必须建立系统的多维评价与验证体系。

5.3.1　“存效”的化学评价指标

利用如UPLC-Q-TOF-MS等高分辨质谱或代谢组学技术, 建立生物技术干预前后药材的全景化学指纹图谱与代谢物轮廓差异评价体系^{[126, 127]}。关注处理前后黄酮类、萜类、酚酸类等次生代谢物群的绝对含量保留率及成分群间的相对比例, 总结生物技术处理后的代谢流变化, 并确认是否产生新的有害代谢物。

5.3.2　“存效”的生物学验证方法

在化学等效性论证的基础上, 引入与传统临床适应症相匹配的生物学验证体系^[128]。体外层面, 针对马兜铃属清肺降气、利水消肿的传统功效, 可通过细胞模型实验进行药效验证, 如气道平滑肌细胞模型验证平喘作用, 肾小管上皮细胞模型验证利水与脱毒情况。体内层面, 可构建能反映传统中医药证候的动物模型, 如肺热咳喘模型、风湿痹痛模型等, 通过观测病理组织学改变、炎症因子水平及各项生化指标, 对比减毒前后在靶器官改善上的等效性。

5.3.3　与传统中药药效一致性验证

由于含马兜铃酸类的中药常在中药方剂中使用, 因此转化为安全药源后还须验证其是否违背传统中医基础理论。或可采用网络药理学与转录组学联合分析, 阐明减毒前后药材对机体核心治疗靶点和信号通路网络的影响^{[129, 130]}。以此证实, 现代生物技术靶向减少或降解马兜铃酸, 仅仅是剥离了引发毒副作用的旁路干扰因子, 而未破坏中药多靶点、多途径协同发挥“清热、利水、止痛”的系统网络, 从而在微观分子机制上确证了其与传统中医药学临床用药经验的契合性。

6　总结与展望

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本文以马兜铃等有毒中药为例, 探讨了现代生物技术在资源开发与安全性控制中的潜在价值, 首次提出通过基因编辑、细胞工程、酶工程与发酵工程等现代生物技术干预毒性成分合成及降解, 以期实现有毒中药的“减毒存效”。这一研究思路将传统的中药减毒研究重心由产后外源干预转向产中与产前内源调控, 为破解有毒中药因毒废药的困境提供了具有前瞻性的技术范式。文章还探讨了基于多组学和病理模型的系统评价验证体系, 为有毒中药的安全性控制与药效保留提供了实践路径。

然而, 作为一种新兴策略, 其在现阶段仍存在一定局限。由于中药多成分协同起效的复杂性, 靶向干预特定毒性合成通路对整体药效的潜在影响尚需系统的验证与评估。同时, 部分有毒物质的完整合成网络仍有待进一步解析, 加之生物技术从实验室向工业化发展时所面临的工艺稳定性等问题, 相关应用仍需在后续实践中不断完善。

针对以上局限, 未来的具体研究方向可聚焦以下四个方面。第一, 进一步开展有效与有毒成分合成途径的基础研究, 明确毒性物质与活性成分的合成网络及关键节点。第二, 运用现有生物技术方法, 提高调控的准确度, 在保留整体药效物质的前提下, 培育表型稳定的低毒或无毒种质资源, 或筛选适合放大生产的降解菌株。第三, 建立更为完善的系统评价标准, 结合病证结合动物模型, 对应用生物技术处理后的药材进行药理与毒理学验证, 为新型减毒工艺的实际应用提供科学参考。第四, 通过厘清药材基原与精准识别毒性组分, 系统解析其致毒机制、量效关系与构效关系, 明确药物起效与致毒的剂量窗口及安全范围, 为后续的精准减毒研究与临床合理用药提供支撑。

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2026年第61卷第8期

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doi: 10.16438/j.0513-4870.2026-0261

接收时间：2026-03-10
首发时间：2026-09-21
出版时间：2026-08-12

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收稿日期：2026-03-10
修回日期：2026-05-12

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¹南京中医药大学药学院, 江苏南京 210023

³中国中医科学院, 道地药材品质保障与资源持续利用全国重点实验室, 北京 100700

⁴南京中医药大学第一临床学院, 江苏南京 210023

通讯作者:

濮春娟, E-mail: puchunjuan@njucm.edu.cn

吴啟南, E-mail: wuqn@njucm.edu.cn

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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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Edition of the Chinese Pharmacopoeia	Deletion and revision of traditional Chinese medicinal materials varieties	Deletion and revision of Chinese patent medicine varieties	Reasons for deletion and revision
2005	Caulis Aristolochiae Manshuriensis, Radix Aristolochiae Fangchi, Radix Aristolochiae^[7], the medicinal part of Herba Asari was revised from "whole herb" to "root and rhizome"^[8]	All proprietary preparations containing Caulis Aristolochiae Manshuriensis, Radix Aristolochiae Fangchi, or Radix Aristolochiae were uniformly replaced with Caulis Akebiae (Lardizabalaceae), Radix Stephaniae Tetrandrae (Menispermaceae), and Radix Inulae (Asteraceae)^[8]	Based on high attention to drug safety and consideration of potential risks of hepatorenal toxicity^[9]
2010	None^[10]	None^[10]	No variety deletion was made in Volume I of this edition of the Pharmacopoeia
2015	Hominis Placenta^[11]	Pediatric Diarrhea External Powder, Shengxue Wan, Ankun Zanyu Wan, Heche Dazao Wan, Bushen Guchi Wan, Yixuesheng Capsule^[11]	Based on considerations of safety, efficacy, quality controllability^[12] and protection of endangered species^[13]
2020	Frucutus Aristolochiae, Herba Aristolochiae, Manis Squama^[14]	Huanglian Yanggan Wan^[14]	Based on considerations of wild resources, ethical issues^[15] and the results of special studies on the dose-effect relationship of traditional Chinese medicine components and toxicity^[16]
2025	None^[17]	Jiusheng San, Rongshuan Zaizao Wan, Xiaoying Wan, Wanling Wuxiang Gao, Guiling Ji, Tongru Keli, Zhisou Huatan Wan, Awen Huatan Gao, Tongpian Pian, Zaizao Wan, Badu Gao, Tongbi Jiaonang, Zhuye Datan Wan, Jinpu Jiaonang, Shexiang Naimaikang Jiaonang, Yangdan Wan, Huixiang Juhe Wan, Fuke Tongjing Wan, Huhun Wine^[17]	No longer include Chinese patent medicines using wild endangered animals and plants as raw materials, Chinese patent medicines that have not been used clinically for a long time without approval numbers, and Chinese patent medicines with potential safety issues^[18]

Edition of the Chinese Pharmacopoeia

Deletion and revision of traditional Chinese medicinal materials varieties

Deletion and revision of Chinese patent medicine varieties

Reasons for deletion and revision

2005

Caulis Aristolochiae Manshuriensis, Radix Aristolochiae Fangchi, Radix Aristolochiae^[7], the medicinal part of Herba Asari was revised from "whole herb" to "root and rhizome"^[8]

All proprietary preparations containing Caulis Aristolochiae Manshuriensis, Radix Aristolochiae Fangchi, or Radix Aristolochiae were uniformly replaced with Caulis Akebiae (Lardizabalaceae), Radix Stephaniae Tetrandrae (Menispermaceae), and Radix Inulae (Asteraceae)^[8]

Based on high attention to drug safety and consideration of potential risks of hepatorenal toxicity^[9]

2010

None^[10]

No variety deletion was made in Volume I of this edition of the Pharmacopoeia

2015

Hominis Placenta^[11]

Pediatric Diarrhea External Powder, Shengxue Wan, Ankun Zanyu Wan, Heche Dazao Wan, Bushen Guchi Wan, Yixuesheng Capsule^[11]

Based on considerations of safety, efficacy, quality controllability^[12] and protection of endangered species^[13]

2020

Frucutus Aristolochiae, Herba Aristolochiae, Manis Squama^[14]

Huanglian Yanggan Wan^[14]

Based on considerations of wild resources, ethical issues^[15] and the results of special studies on the dose-effect relationship of traditional Chinese medicine components and toxicity^[16]

2025

None^[17]

Jiusheng San, Rongshuan Zaizao Wan, Xiaoying Wan, Wanling Wuxiang Gao, Guiling Ji, Tongru Keli, Zhisou Huatan Wan, Awen Huatan Gao, Tongpian Pian, Zaizao Wan, Badu Gao, Tongbi Jiaonang, Zhuye Datan Wan, Jinpu Jiaonang, Shexiang Naimaikang Jiaonang, Yangdan Wan, Huixiang Juhe Wan, Fuke Tongjing Wan, Huhun Wine^[17]

No longer include Chinese patent medicines using wild endangered animals and plants as raw materials, Chinese patent medicines that have not been used clinically for a long time without approval numbers, and Chinese patent medicines with potential safety issues^[18]