Biotransformation patterns of dictamnine in vitro/in vivo and its relative molecular mechanism of dictamnine-induced acute liver injury in mice

Lin, Qiuxia; Guan, Huida; Ma, Chao; Chen, Liangni; Cao, Lanlan; Liu, Hanze; Cheng, Xuemei; Wang, Changhong

doi:10.1016/j.etap.2021.103628

Cited by 4 publications

(4 citation statements)

References 35 publications

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“…Several studies have shown that the furan ring can be metabolized by CYP3A4 to generate active intermediates that can combine with GSH, resulting in GSH depletion and hepatotoxicity [ 28 , 29 , 30 ]. As the main components of Dictamnus dasycarpus , furoquinoline alkaloids can be metabolized to dihydrofuroquinoline alkaloids by CYP3A4, consuming GSH simultaneously [ 31 , 32 ].…”

Section: Discussionmentioning

confidence: 99%

Exploring the Mechanism of Hepatotoxicity Induced by Dictamnus dasycarpus Based on Network Pharmacology, Molecular Docking and Experimental Pharmacology

et al. 2023

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The root bark of Dictamnus dasycarpus Turcz is a traditional Chinese medicine, Dictamni Cortex (DC), which is mainly used in the clinical treatment of skin inflammation, eczema, rubella, rheumatism, and gynecological inflammation. Unexpectedly, there are some cases of liver injury after the administration of DC. However, the mechanism of hepatotoxicity remains ambiguous. The aim of this study was to explore the mechanism and substance bases of DC hepatotoxicity based on network pharmacology and molecular docking, verified through pharmacological experiments. Partial prototype components and metabolites in vivo of quinoline alkaloids from DC were selected as candidate compounds, whose targets were collected from databases. Network pharmacology was applied to study the potential hepatotoxic mechanism after correlating the targets of candidate compounds with the targets of hepatotoxicity. Molecular docking was simulated to uncover the molecular mechanism. Furthermore, the hepatotoxicity of the extract and its constituents from DC was evaluated in vivo and in vitro. We constructed the “potential toxic components-toxic target-toxic pathway” network. Our results showed that the targets of DC included CYP1A2 and GSR, participating in heterologous steroid metabolism, REDOX metabolism, drug metabolism, heterocyclic metabolic processes, the synthesis of steroid hormone, cytochrome P450 metabolism, chemical carcinogens and bile secretion pathways. In vitro and in vivo experiments displayed that DC could result in a decrease in GSH-Px and oxidative stress, simultaneously inhibiting the expression of CYP1A2 and inducing hepatotoxicity. These results further indicated the mechanism of hepatotoxicity induced by Dictamnus dasycarpus, providing a basic theory to explore and prevent hepatotoxicity in the clinical usage of Dictamnus dasycarpus.

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Section: Discussionmentioning

confidence: 99%

Exploring the Mechanism of Hepatotoxicity Induced by Dictamnus dasycarpus Based on Network Pharmacology, Molecular Docking and Experimental Pharmacology

et al. 2023

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“…Over 60 severe even fatal hepatotoxicity cases after ingesting DC have been reported worldwide, and DIC, as the major bioactive component, was speculated to be correlated with DC-induced liver injury. Oxidative stress injury and NF-κB mediated inflammation were reported to be involved in DIC-induced acute liver injury in mice (Lin et al, 2021).…”

Section: Dictamninementioning

confidence: 99%

“…Study on the metabolism of DIC in respective systems containing liver microsomes across various species found that the furan ring could be oxidized to 2,3-epoxide primarily mediated by CYP3A4 (Wang et al, 2016) vivo, which may be responsible for its toxicities (Feng et al, 2016;Lin et al, 2021). To evaluate the role of metabolic activation in DIC-induced liver injury, primary human hepatocytes, L02, HepG2 cells were chosen as the models.…”

Section: Dictamninementioning

confidence: 99%

Metabolic Activation and Hepatotoxicity of Furan-Containing Compounds

2022

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Furan-containing compounds are abundant in nature, of which many but not all have been found to be hepatotoxic and carcinogenic. The furan ring present in the chemical structures may be one of the domineering factors to bring about the toxic response resulting from the generation of reactive epoxide or cis-enedial intermediates which are of the potential to react with biomacromolecules. This review sets out to explore the relationship between the metabolic activation and hepatotoxicity of furan-containing compounds on the strength of scientific reports on several typical alkylated furans, synthetic pharmaceuticals and components extracted from herbal medicines. The pharmacological activities as well as concrete evidence of their liver injuries are described, and the potential toxic mechanisms were discussed partly based on our previous work. Efforts were made to understand the development of liver injury and seek solutions to prevention and interference of the adverse effects.

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“…DIC contains a furan moiety and is a furoquinoline alkaloid (Huang et al, 2020). The furan moiety of DIC could be mediated by cytochrome P4503A (CYP3A) to form an epoxide metabolite (Lin et al, 2021; Shi et al, 2019). DIC‐derived epoxide intermediate was correlated with DIC‐induced hepatotoxicity, and the selective hydrogenation of the furan moiety of DIC could eliminate its toxicity (Shi et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Protection of schisantherin A against dictamnine‐induced hepatotoxicity: Pharmacokinetic insights

Chang,

Li,

Yang

et al. 2023

J of Applied Toxicology

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Dictamnine (DIC), as the most abundant furoquinoline alkaloid ingredient of the herbal medicine Cortex Dictamni (CD), can induce severe liver injury. A previous study found that DIC‐induced liver injury was initiated by cytochrome P4503A (CYP3A)‐mediated metabolic activation and subsequent formation of adducts with cellular proteins. Schisantherin A (SchA) is the major lignan component of the herbal medicine Schisandra chinensis (SC). SC is frequently combined with CD used in numerous Chinese medicinal formulas for the treatment of eczema and urticaria. Furthermore, SC could protect against CD‐induced hepatotoxicity. The objective of the study was to investigate the protective effect of SchA on DIC‐induced hepatotoxicity based on pharmacokinetic interactions. The studies found that SchA exerted a protective effect on DIC‐induced hepatotoxicity in a dose‐dependent manner. Pharmacokinetic studies showed that pretreatment with SchA enhanced the area under concentration‐time curve (AUC) and maximal concentration (Cmax) values of DIC in the serum and liver tissue of mice, indicating that SchA could augment the accumulation of DIC in the circulation. In vitro metabolism assays with mouse liver microsomes (MLMs) showed that SchA reduced the production of DIC–glutathione (GSH) conjugate. In addition, SchA significantly reduced the excretion of DIC–GSH conjugate in the urine of mice and relieved hepatic GSH depletion induced by DIC. These results suggested that SchA could inhibit the metabolic activation of DIC in vitro and in vivo. In summary, our findings showed that the observed pharmacokinetic interactions might be attributable to the inhibition of the metabolism of DIC by SchA, which might be responsible for the protection of SchA against DIC‐induced hepatotoxicity. Therefore, the development of a standardized combination of DIC and SchA may protect patients from DIC‐induced liver injury.

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Biotransformation patterns of dictamnine in vitro/in vivo and its relative molecular mechanism of dictamnine-induced acute liver injury in mice

Cited by 4 publications

References 35 publications

Exploring the Mechanism of Hepatotoxicity Induced by Dictamnus dasycarpus Based on Network Pharmacology, Molecular Docking and Experimental Pharmacology

Exploring the Mechanism of Hepatotoxicity Induced by Dictamnus dasycarpus Based on Network Pharmacology, Molecular Docking and Experimental Pharmacology

Metabolic Activation and Hepatotoxicity of Furan-Containing Compounds

Protection of schisantherin A against dictamnine‐induced hepatotoxicity: Pharmacokinetic insights

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