Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
Pharmacy Academy, Harbin University of Commerce, Harbin, 150076, China.
Acta Pharmacol Sin. 2018 Dec;39(12):1923-1934. doi: 10.1038/s41401-018-0012-z. Epub 2018 May 23.
Timosaponin A3, a saponin in Zhimu, elicited hepatotoxicity via oxidative stress. However, the clinical medication of Zhimu has been historically regarded as safe, probably associated with the antioxidants it contains. However, the related information on the in vivo levels of timosaponin A3 and antioxidants remained unclear on Zhimu treatments. Therefore, a combination of the in vitro metabolism, including microbiota-mediated and liver-mediated metabolism, and in vivo pharmacokinetics and hepatic disposition, was conducted for three xanthones (neomangiferin, mangiferin, and norathyriol) and three saponins (timosaponin B2, timosaponin B3, and timosaponin A3) on Zhimu treatments. Consequently, following oral administration of Zhimu decoction to rats, those saponins and xanthones were all observed in the plasma with severe liver first-pass effect, where mangiferin was of the maximum exposure. Despite the ignorable content in the herb, timosaponin A3 elicited sizable hepatic exposure as the microbiota-mediated metabolite of saponins in Zhimu. The similar phenomenon also occurred to norathyriol, the microbiota-mediated metabolite of xanthones. However, the major prototypes in Zhimu were of limited hepatic exposure. We deduced the hepatic collection of norathyriol, maximum circulating levels of mangiferin, and timosaponin B2 and mangiferin interaction may directly or indirectly contribute to the whole anti-oxidation of Zhimu, and then resisted the timosaponin A3-induced hepatotoxicity. Thus, our study exploratively interpreted the discrepancy between herbal safety and timosaponin A3-induced hepatotoxicity. However, given the considerable levels and slow eliminated rate of timosaponin A3 in the liver, more attention should be paid to the safety on the continuous clinical medication of Zhimu in the future.
知母中的知母皂苷 A3 通过氧化应激引起肝毒性。然而，知母的临床用药一直被认为是安全的，这可能与它所含的抗氧化剂有关。然而，关于知母治疗时知母皂苷 A3 和抗氧化剂的体内水平的相关信息尚不清楚。因此，我们对三种黄烷酮（新芒果苷、芒果苷和异芒果苷）和三种皂苷（知母皂苷 B2、知母皂苷 B3 和知母皂苷 A3）进行了体外代谢（包括微生物群介导和肝脏介导的代谢）和体内药代动力学及肝处置的研究。因此，大鼠口服知母汤后，这些皂苷和黄烷酮均在血浆中被观察到，且肝脏首过效应严重，其中芒果苷的暴露量最大。尽管在草药中的含量可以忽略不计，但知母皂苷 A3 作为知母中皂苷的微生物群介导的代谢物，引起了可观的肝暴露。黄烷酮的微生物群介导的代谢物异芒果苷也出现了类似的现象。然而，知母中的主要原型的肝暴露有限。我们推断，异芒果苷的肝摄取、芒果苷的最大循环水平以及知母皂苷 B2 和芒果苷的相互作用可能直接或间接有助于知母的整体抗氧化作用，从而抵抗知母皂苷 A3 引起的肝毒性。因此，我们的研究探索性地解释了草药安全性与知母皂苷 A3 引起的肝毒性之间的差异。然而，鉴于知母皂苷 A3 在肝脏中的水平相当高且消除速度较慢，在未来的临床用药中，应更加关注知母的安全性。
