Department of Biochemistry, University of California, 900 University Ave, Riverside, CA 92521, USA.
Genes (Basel). 2024 Sep 30;15(10):1287. doi: 10.3390/genes15101287.
Triptolide, a bioactive diterpene tri-epoxide extracted from Hook F (TWHF), exhibits notable pharmacological activities, including anti-inflammatory, immunosuppressive, antifertility, and anticancer effects. Despite its promising therapeutic potential, clinical applications of triptolide are significantly limited by its poor water solubility and substantial toxicity, particularly hepatotoxicity, nephrotoxicity, and cardiotoxicity. These toxic effects are difficult to separate from many of its desired therapeutic effects, the Yin and Yang of triptolide applications. Triptolide's therapeutic and toxic effects are linked to its inhibitory interactions with XPB, a DNA helicase essential for transcription by RNA polymerase II (RNAPII) and nucleotide excision repair (NER). By irreversibly binding to XPB, triptolide inhibits its ATPase activity, leading to global repression of transcription and impaired NER, which underlies its cytotoxic and antitumor properties. Recent developments, including triptolide prodrugs such as Minnelide and derivatives like glutriptolides, aim to enhance its pharmacokinetic properties and reduce toxicity. This review critically examines triptolide's chemical structure, therapeutic applications, toxicological profile, and molecular interactions with XPB and other protein targets to inform future strategies that maximize therapeutic efficacy while minimizing adverse effects.
雷公藤红素，一种从卫矛科雷公藤属植物（TWHF）中提取的生物活性二萜三环氧，具有显著的药理活性，包括抗炎、免疫抑制、抗生育和抗癌作用。尽管雷公藤红素具有很大的治疗潜力，但由于其较差的水溶性和较大的毒性，特别是肝毒性、肾毒性和心脏毒性，其临床应用受到了显著限制。这些毒性作用与其许多所需的治疗作用很难分开，这是雷公藤红素应用的“阴阳”两面。雷公藤红素的治疗和毒性作用与其对 XPB 的抑制相互作用有关，XPB 是 RNA 聚合酶 II（RNAPII）和核苷酸切除修复（NER）转录所必需的 DNA 解旋酶。通过不可逆地与 XPB 结合，雷公藤红素抑制其 ATP 酶活性，导致转录的全局抑制和 NER 受损，这是其细胞毒性和抗肿瘤特性的基础。最近的发展，包括雷公藤红素前药如 Minnelide 和衍生物如谷甾醇，旨在增强其药代动力学特性并降低毒性。这篇综述批判性地检查了雷公藤红素的化学结构、治疗应用、毒理学概况以及与 XPB 和其他蛋白质靶标的分子相互作用，为未来的策略提供信息，这些策略旨在最大限度地提高治疗效果，同时最大限度地减少不良反应。
