Development of a mechanism-based biomarker for Dioscorea bulbifera L. exposure and hepatotoxicity in rats

Hu, Zixia; Zhao, Yanjia; Yang, Yi; Li, Wei; Tan, Rong; Zhao, Linhua; Tong, Xiaolin; Peng, Ying; Zheng, Jiang

doi:10.1016/j.phymed.2022.154172

Cited by 6 publications

(5 citation statements)

References 17 publications

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“…The mean serum concentration versus the time profile of DBB with or without GA pretreatment was displayed in Figure 5. with cysteine and/or lysine residues of hepatic proteins to form pyrrole and/or pyrrolinone derivatives (Hu et al, 2022;Wang et al, 2017). In our study, DBB-derived lysine conjugates from the digestion of pyrrolinone-protein adducts were detected, and the results showed that GA reduced DBB-derived pyrrolinone-protein adducts in a dose-dependent manner (Figures 1, 7, and S2).…”

Section: Effect Of Ga On Toxicokinetic Behavior Of Dbbsupporting

confidence: 51%

“…DBB‐induced hepatotoxicity was initiated by CYP3A4‐mediated metabolic activation and subsequent formation of adducts with cellular proteins. DBB‐derived cis‐ enedial intermediate could covalently bind with cysteine and/or lysine residues of hepatic proteins to form pyrrole and/or pyrrolinone derivatives (Hu et al, 2022; Wang et al, 2017). In our study, DBB‐derived lysine conjugates from the digestion of pyrrolinone‐protein adducts were detected, and the results showed that GA reduced DBB‐derived pyrrolinone‐protein adducts in a dose‐dependent manner (Figures 1, 7, and S2).…”

Section: Resultsmentioning

confidence: 99%

“…Our previous study found that the cis ‐enedial intermediate of DBB formed by CYP3A4 played an important role in DBB‐induced liver injury (Figure 1) (Li et al, 2016; Lin et al, 2014). It has been reported that the protein adducts of DBB‐derived cis ‐enedial intermediate with cysteine and/or lysine residues of hepatic proteins were responsible for DBB‐induced hepatotoxicity (Hu et al, 2022; Wang et al, 2017). The preliminary studies found that ketoconazole (a P450 3A inhibitor) not only protected from DBB‐induced hepatotoxicity but also suppressed the formation of reactive metabolites of DBB in vitro and in vivo (Li et al, 2016; Lin et al, 2014), indicating the correlation of the metabolic activation of DBB with its hepatotoxicity.…”

Section: Introductionmentioning

confidence: 99%

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Glycyrrhetinic acid ameliorates diosbulbin B‐induced hepatotoxicity in mice by modulating metabolic activation of diosbulbin B

Lin

Liu

Chang

et al. 2023

J of Applied Toxicology

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Exposure to diosbulbin B (DBB), the primary component of the herbal medicine Dioscorea bulbifera L. (DB), can cause liver injury in humans and experimental animals. A previous study found DBB‐induced hepatotoxicity was initiated by CYP3A4‐mediated metabolic activation and subsequent formation of adducts with cellular proteins. The herbal medicine licorice (Glycyrrhiza glabra L.) is frequently combined with DB used in numerous Chinese medicinal formulas in an effort to protect against DB‐elicited hepatotoxicity. Importantly, glycyrrhetinic acid (GA), the major bioactive ingredient in licorice, inhibits CYP3A4 activity. The study aimed to investigate the protection of GA against DBB‐induced hepatotoxicity and the underlying mechanism. Biochemical and histopathological analysis showed GA alleviated DBB‐induced liver injury in a dose‐dependent manner. In vitro metabolism assay with mouse liver microsomes (MLMs) indicated that GA decreased the generation of metabolic activation‐derived pyrrole‐glutathione (GSH) conjugates from DBB. Toxicokinetic studies demonstrated that GA increased maximal serum concentration (Cmax) and area under the serum–time curve (AUC) of DBB in mice. In addition, GA attenuated hepatic GSH depletion caused by DBB. Further mechanistic studies showed that GA reduced the production of DBB‐derived pyrroline‐protein adducts in a dose‐dependent manner. In conclusion, our findings demonstrated that GA exerted protective effect against DBB‐induced hepatotoxicity, mainly correlated with suppressing the metabolic activation of DBB. Therefore, the development of a standardized combination of DBB with GA may protect patients from DBB‐induced hepatotoxicity.

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Section: Effect Of Ga On Toxicokinetic Behavior Of Dbbsupporting

confidence: 51%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Glycyrrhetinic acid ameliorates diosbulbin B‐induced hepatotoxicity in mice by modulating metabolic activation of diosbulbin B

Lin

Liu

Chang

et al. 2023

J of Applied Toxicology

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“…Apart from hepatotoxicity, furan has been categorized as “possibly carcinogenic to humans” by the International Agency for Research on Cancer (IARC), prompting significant concern regarding the detection of this substance naturally occurring in food. Plasma protein covalent modification by reactive metabolites of DSB can be used as a biomarker for Dioscorea bulbifera L. exposure and hepatotoxicity in rats [69] . In addition, an analytical platform was developed to screen cis -enediones ( cis -enedials or γ -ketoenals) resulting from the metabolic activation of potentially harmful furans by employing GSH and 4-bromobenzylamine (BBA) as trapping agents, yielding GSH/BBA-derived pyrroles in the incubation system.…”

Section: Metabolic Activation Of Natural Products In Tcmmentioning

confidence: 99%

Chemical nature of metabolic activation of natural products in traditional Chinese medicines possibly associated with toxicities

Liu,

Wang,

Liu

et al. 2024

Acupuncture and Herbal Medicine

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Ensuring the safety of traditional Chinese medicines (TCM) has perennially presented a universal challenge in the healthcare realm. Meticulous investigations into the toxicological intricacies of natural products are of paramount significance, particularly regarding the metabolic transformation of these substances and the subsequent generation of reactive intermediates. This biochemical process underlies the genesis of diverse toxic manifestations, including hepatotoxicity, nephrotoxicity, pulmonary toxicity, and genotoxicity. Compounds sorted within TCM, including pyrrolizidine alkaloids, anthraquinones, furanoterpenoids, alkenylbenzenes, bisbenzylisoquinoline alkaloids, flavonoids, and methylenedioxyphenyl derivatives, evince a spectrum of deleterious mechanisms upon metabolic activation. This review provides a comprehensive delineation of the pathways through which these compounds induce toxicity via metabolic activation. This review emphasizes the chemical mechanisms involved in the metabolic activation of natural products that may trigger a toxic cascade, rather than a superficial phenomenon. Furthermore, this study enriches the extant literature by delving into advancements in elucidating the mechanisms of toxicity engendered by metabolic activation. In conclusion, this review highlights the importance of scrutinizing the mechanisms of toxicity and provides insights into the judicious and safe use of TCM.

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“…Dioscorea bulbifera L. (DB), an herbal medicine belonging to the yam family Dioscoreaceae, is extensively used for the treatment of thyroid diseases and a variety of tumors in Asian countries. [ 1–4 ] In spite of DB has a wide variety of therapeutical values, the adverse effects of DB have also attracted the attention of people. Numerous liver injury cases in the clinical application have been documented.…”

Section: Introductionmentioning

confidence: 99%

Glycyrrhizin protects against diosbulbin B‐induced hepatotoxicity by inhibiting the metabolic activation of diosbulbin B

Yang,

Liu,

Chang

et al. 2023

J Biochem & Molecular Tox

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Diosbulbin B (DIOB), isolated from herbal medicine Dioscorea bulbifera L. (DB), could induce severe liver injury, and its toxicology was closely associated with CYP3A4‐mediated metabolic oxidation of furan moiety to the corresponding cis‐enedial reactive metabolite. Glycyrrhizin (GL), the major bioactive ingredient in licorice, can inhibit the activity of CYP3A4. Thus, GL may ameliorate hepatotoxicity of DIOB when GL and DIOB are co‐administrated. The study aimed to investigate the protective effect of GL on DIOB‐induced hepatotoxicity and the underlying mechanism. Biochemical and histopathological analysis demonstrated that GL alleviated DIOB‐induced hepatotoxicity in a dose‐dependent manner. In vitro study with mouse liver microsomes (MLMs) demonstrated that GL reduced the formation of metabolic activation‐derived pyrrole‐glutathione (GSH) conjugates from DIOB. Toxicokinetic studies showed that the pretreatment with GL caused the increase of AUCs and Cmax of DIOB in blood of mice, resulting in accelerating the accumulation of DIOB in the circulation. In addition, the pretreatment with GL alleviated DIOB‐induced hepatic GSH depletion. In summary, GL ameliorated DIOB‐induced hepatotoxicity, possibly related to the inhibition of the metabolic activation of DIOB. Thus, development of a standardized combination of DIOB with GL may protect patients from DIOB‐induced liver injury.

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Development of a mechanism-based biomarker for Dioscorea bulbifera L. exposure and hepatotoxicity in rats

Cited by 6 publications

References 17 publications

Glycyrrhetinic acid ameliorates diosbulbin B‐induced hepatotoxicity in mice by modulating metabolic activation of diosbulbin B

Glycyrrhetinic acid ameliorates diosbulbin B‐induced hepatotoxicity in mice by modulating metabolic activation of diosbulbin B

Chemical nature of metabolic activation of natural products in traditional Chinese medicines possibly associated with toxicities

Glycyrrhizin protects against diosbulbin B‐induced hepatotoxicity by inhibiting the metabolic activation of diosbulbin B

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