Quantitative Evaluation of the Compatibility Effects of Huangqin Decoction on the Treatment of Irinotecan-Induced Gastrointestinal Toxicity Using Untargeted Metabolomics

Abstract

Huangqin decoction (HQD), a traditional Chinese medicine (TCM), has been widely used to treat gastrointestinal syndrome in China for thousands of years. Chemotherapy drug irinotecan (CPT-11) is used clinically to treat various kinds of cancers but limited by its side effects, especially delayed diarrhea. Nowadays, HQD has been proved to be effective in attenuating the intestinal toxicity induced by CPT-11. HQD consists of four medicinal herbs including Scutellaria baicalensis Georgi, Glycyrrhiza uralensis Fisch, Paeonia lactiflora Pall, and Ziziphus jujuba Mill. Due to its complexity, the role of each herb and the multi-herb synergistic effects of the formula are poorly understood. In order to quantitatively assess the compatibility effects of HQD, mass spectrometry-based untargeted metabolomics studies were performed. The serum metabolic profiles of rats administered with HQD, single S. baicalensis decoction, S. baicalensis-free decoction and baicalin/baicalein combination were compared. A time-dependent trajectory upon principal component analysis was firstly used to visualize the overall differences. Then metabolites deregulation score and relative area under the curve were calculated and used as parameters to quantitatively evaluate the compatibility effects of HQD from the aspect of global metabolic profile and the specifically altered metabolites, respectively. The collective results indicated that S. baicalensis played a crucial role in the therapeutic effect of HQD on irinotecan-induced diarrhea. Both HQD and SS decoction regulated glycine, serine and threonine pathway. This study demonstrated that metabolomics was a promising tool to elucidate the compatibility effects of TCM or combinatorial drugs.

Evidence for Shikonin acting as an active inhibitor of human carboxylesterases 2: Implications for herb–drug combination

“…Although a large number of clinical drugs, such as loperamide vhydrochloride, cholestyramine, and levofloxacin, have been regarded as the promising options for the prevention of delayed diarrhea caused by CPT‐11, the improper mechanism and dosage are common causes for treatment failure (X. Wang et al, ). Moreover, herbal medicine PHY906 has been reported to attenuate the intestinal toxicity induced by CPT‐11 (Cui et al, ; Lam et al, ). PHY906 is composed of four main herbs of which baicalin, a β‐glucuronidase inhibitor, is the most abundant ingredient (Kummar et al, ).…”

“…Various traditional herbal medicines, such as PHY906 (Cui et al, ; Lam et al, ) and saireito (Fujita et al, ), have been reported to attenuate the intestinal toxicity induced by CPT‐11 or 5‐fluorouracil; however, the active ingredient and attenuation mechanism were not identified in those studies. Additionally, flutamide, a nonsteroidal antiandrogen used primarily to treat prostate cancer, is also hydrolyzed by hCE2 to FLU‐1, which can be further metabolized to N‐hydroxy FLU‐1 by human CYP3A4 (Aizawa et al, ; Kobayashi, Fukami, Shimizu, Nakajima, & Yokoi, ).…”

Anti‑diarrheal effect of Scutellaria baicalensis is associated with suppression of smooth muscle in the rat colon

“…Diarrhea is categorized into four types based on its mechanism of action: Osmotic diarrhea, secretory diarrhea, inflammatory and infectious diarrhea, and diarrhea related to motility disorders. Clinically, diarrhea-predominant irritable bowel syndrome and functional diarrhea are associated with alterations in intestinal motility; therefore, some anti-diarrheal agents decreasing intestinal transit, such as opioids and 5-HT 3 antagonist, have been used to manage these diseases (1).…”

“…Scutellaria baicalensis is widely used as a herbal medicine in East Asia and Europe for gastrointestinal tract (GI) disorders including dysentery, diarrhea, and abdominal pain (2). Experimentally, it has anti-diarrheal effect on irrinotecan-induced diarrhea in rats (3). Clinically, it demonstrated an improvement in the diarrhea toxicity grade and reduction of frequency of severe diarrhea in lung cancer patients with irrinotecan-induced diarrhea (4).…”

Macranthoidin B Modulates Key Metabolic Pathways to Enhance ROS Generation and Induce Cytotoxicity and Apoptosis in Colorectal Cancer

“…Moreover, our recent metabolomics study on peiminine, a compound extracted from the bulbs of Fritillaria thunbergii which has been traditionally used in TCM, demonstrated inhibitory effect on CRC cell proliferation by inducing apoptosis and autophagy and modulating key metabolic pathways [14]. In addition, Cui et al [18] recently reported using LC-MS- and GC-MS-based untargeted metabolomics strategy to quantitatively evaluate the effects of Huangqin decoction on irinotecan-induced gastrointestinal toxicity, suggesting a potential application of metabolomics analysis in elucidating the comprehensive mechanisms of action of TCMs or combinations of medications.…”