Institute of Materia Medica, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.
Toxicol Lett. 2010 Feb 1;192(2):212-20. doi: 10.1016/j.toxlet.2009.10.028. Epub 2009 Oct 30.
Triptolide (TP), a major active and toxic component of Tripterygium wilfordii, is reported to be converted into four mono-hydroxylated metabolites (m/z 375) by cytochrome P450 (CYP) in vitro, and CYP3A4 was the primary isoform responsible for its hydroxylation. Dexamethasone (DXM), a CYP3A inducer, is frequently combined with TP in clinical therapy. However, the effects of DXM on the metabolism and toxicity of TP are unknown. In this study, the metabolism of TP was investigated in rat liver microsomes pretreated with DXM. The metabolic profile of TP was significantly altered. The V(max) was about 9.58-fold higher than that of vehicle group and the K(m) was about 3.57-fold higher. With DXM, the amount of metabolite M3 was significantly higher than that with no DXM while M1 and M2 were not found, and a new metabolite (m/z 391) was observed. The liver and the kidney toxicity of TP on rat pretreated with DXM were evaluated. We observed that pretreatment with DXM protected against TP hepatotoxicity. No obvious nephrotoxicity was detected on rats treated with TP, whereas the kidney damage was observed in DXM group and the level of toxicity was much reduced with DXM-TP group. This suggested that TP might decrease nephrotoxicity induced by DXM. These studies indicated that DXM had significant impact on the metabolism and the toxicity of TP as a therapeutic agent.
雷公藤红素（TP）是雷公藤的主要活性和毒性成分，据报道，它在体外可被细胞色素 P450（CYP）转化为四种单羟基化代谢物（m/z 375），CYP3A4 是其羟基化的主要同工酶。地塞米松（DXM）是一种 CYP3A 诱导剂，常与 TP 联合用于临床治疗。然而，DXM 对 TP 代谢和毒性的影响尚不清楚。在这项研究中，我们在经 DXM 预处理的大鼠肝微粒体中研究了 TP 的代谢。TP 的代谢谱发生了显著改变。与对照组相比，最大反应速率（Vmax）约增加了 9.58 倍，米氏常数（K m）约增加了 3.57 倍。在 DXM 存在的情况下，代谢物 M3 的量明显高于无 DXM 存在的情况下，而没有发现 M1 和 M2，并且观察到一种新的代谢物（m/z 391）。我们评估了 DXM 预处理对 TP 肝毒性和肾毒性的影响。我们发现，DXM 预处理可预防 TP 肝毒性。在接受 TP 治疗的大鼠中未检测到明显的肾毒性，而在 DXM 组中观察到肾脏损伤，且 DXM-TP 组的毒性水平显著降低。这表明 TP 可能降低 DXM 引起的肾毒性。这些研究表明，作为一种治疗药物，DXM 对 TP 的代谢和毒性有显著影响。
