Guggulipid is known to be useful for hypercholesterolemia, arthritis, acne, and obesity. These activities are attributed to its two principal isomeric active constituents, viz., E- and Z-guggulsterones. There are several side effects reported for guggulipid, which include widespread erythematous papules in a morbilliform pattern and macules localized to the arms; swelling and erythema of the face with burning sensation; pruritis; and bullous lesions on the lower legs with associated headaches, myalgia and itching. We hypothesized that one probable reason for these toxic reactions could be the formation of electrophilic reactive metabolites (RMs) of guggulsterones and their subsequent reaction with cellular proteins. Unfortunately, no report exists in the literature highlighting detection of RMs of guggulsterone isomers. Accordingly, the present study was undertaken to investigate the potential of E- and Z-guggulsterones to form RMs in human liver microsomes (HLM) using glutathione (GSH) and N-acetylcysteine (NAC) as trapping agents. The generated samples were analysed using ultra-high performance liquid chromatography (UHPLC) coupled to an Orbitrap mass spectrometer. The analysis of incubations with trapping agents highlighted that hydroxylated metabolites of guggulsterone isomers showed adduction with GSH and NAC. Even direct adducts of guggulsterone isomers were observed with both the trapping agents. The in silico toxicity potential of E- and Z-guggulsterones and their RMs was predicted using ADMET Predictor™ software and comparison was made against reported toxicities of guggulipid.

中文翻译：

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使用UHPLC-Orbitrap质谱仪体外评估人肝微粒体中E-和Z-古古甾酮及其代谢产物的反应性

已知古吉利特可用于高胆固醇血症，关节炎，痤疮和肥胖症。这些活性归因于其两个主要的异构活性成分，即E-和Z-古古甾酮。据报道，对于古吉利特脂有几种副作用，包括呈麻疹状的广泛性红斑丘疹和位于臂部的黄斑。灼热感使面部肿胀和红斑；瘙痒 小腿大疱性病变，伴有头痛，肌痛和瘙痒。我们假设这些毒性反应的可能原因之一可能是古古甾酮的亲电反应性代谢物（RMs）的形成以及它们随后与细胞蛋白的反应。不幸的是，在文献中没有报告强调检测古古甾酮异构体的RM。因此，本研究旨在利用谷胱甘肽（GSH）和N-乙酰半胱氨酸（NAC）作为捕集剂，研究E-和Z-古古甾酮在人肝微粒体（HLM）中形成RM的潜力。使用与Orbitrap质谱仪耦合的超高效液相色谱（UHPLC）分析生成的样品。诱捕剂孵育的分析表明，古古斯通异构体的羟基化代谢产物显示出与GSH和NAC的加合。两种捕获剂甚至都可以观察到古古甾酮异构体的直接加合物。使用ADMET Predictor™软件预测了E-和Z-古格甾酮及其RM的计算机毒性潜力，并与已报道的古格氏脂质毒性进行了比较。