Discovery of Hepatotoxic Equivalent Combinatorial Markers from Dioscorea bulbifera tuber by Fingerprint-Toxicity Relationship Modeling

Abstract

Due to extremely chemical complexity, identification of potential toxicity-related constituents from an herbal medicine (HM) still remains challenging. Traditional toxicity-guided separation procedure suffers from time- and labor-consumption and neglects the additive effect of multi-components. In this study, we proposed a screening strategy called “hepatotoxic equivalent combinatorial markers (HECMs)” for a hepatotoxic HM, Dioscorea bulbifera tuber (DBT). Firstly, the chemical constituents in DBT extract were globally characterized. Secondly, the fingerprints of DBT extracts were established and their in vivo hepatotoxicities were tested. Thirdly, three chemometric tools including partial least squares regression (PLSR), back propagation-artificial neural network (BP-ANN) and cluster analysis were applied to model the fingerprint-hepatotoxicity relationship and to screen hepatotoxicity-related markers. Finally, the chemical combination of markers was subjected to hepatotoxic equivalence evaluation. A total of 40 compounds were detected or tentatively characterized. Two diterpenoid lactones, 8-epidiosbulbin E acetate (EEA) and diosbulbin B (DIOB), were discovered as the most hepatotoxicity-related markers. The chemical combination of EEA and DIOB, reflecting the whole hepatotoxicity of original DBT extract with considerable confidential interval, was verified as HECMs for DBT. The present study is expected not only to efficiently discover hepatotoxicity-related markers of HMs, but also to rationally evaluate/predict the hepatotoxicity of HMs.

Development of Allergenicity and Toxicity Assessment Methods for Evaluating Transgenic Sugarcane Overexpressing Sucrose–Phosphate Synthase

“…The sucrose contents were determined according to the assumptions of 15% sucrose content in sugarcane juice [30]. To substitute the sugarcane juice injection at group I, the mice were administered by oral gavage of 0.5% CMC-Na suspension according to a method previously described [31]. The mice were not fed for 12 h before treatment induction [21,31].…”

“…To substitute the sugarcane juice injection at group I, the mice were administered by oral gavage of 0.5% CMC-Na suspension according to a method previously described [31]. The mice were not fed for 12 h before treatment induction [21,31]. All mice were observed for signs of toxicity (piloerection, motor activity, vocal tremor, and feces) during 4 h after treatments and daily for 14 days.…”

Potential Hepatotoxins Found in Herbal Medicinal Products: A Systematic Review

“…Among toxic terpenoids, triptolide from Tripterygium wilfordii , toosendanin from Melia toosendan , lantadenes A and B from Lanata camra are the most frequently reported compounds capable of inducing liver injury. By in vitro and in vivo assays, terpenoid lactones found in Dioscorea bulbifera , Helenium aromaticum , Telekia speciosa , Aucklandia lappa , and Inula helenium have been shown to be involved in the stimulation of glutathione peroxidase activity and reduction of glutathione levels which in turn may trigger the initiation and progress of liver injury [ 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 ].…”

Intracellular Accumulation as an Indicator of Cytotoxicity to Screen Hepatotoxic Components of Chelidonium majus L. by LC–MS/MS

“…Nevertheless, a common drawback of the above experimental and computational methods is that the hepatotoxicity of each compound is evaluated individually with ignorance of the synergistic effects of multiple constituents in TCMs. Recently, fingerprint-toxicity modeling methods have been employed to screen the major hepatotoxic components in Euodia rutaecarpa , D. bulbifera , and P. multiflorum [8,9,10]. These methods are based on the characterization of the correlations between characteristic chromatographic peaks and the holistic hepatotoxicity of TCMs by multivariate statistical analysis.…”