Metabolism of the Hepatotoxic Compound Sophoraflavanone G in Rat Liver Microsomes

Chen, Ping; Zhang, Xiuwen; Huang, Tao‐Min; Yu, Qianqian; Cheng, Ni

doi:10.1111/1750-3841.12501

Cited by 6 publications

(4 citation statements)

References 33 publications

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“…It is well known that the pharmacokinetic and bioavailability study of a bioactive constituent can help us to understand its in vivo behavior and actions . To date, a few studies have investigated the metabolism and pharmacokinetics of a single component of the prenylated flavonoids in S. flavescens . However, the treatment of diseases by traditional Chinese medicine is based on the interactions of multiple ingredients .…”

Section: Introductionmentioning

confidence: 99%

Determination of sophoraflavanone G and kurarinone in rat plasma by UHPLC–MS/MS and its application to a pharmacokinetic study

Yang

Zhang

et al. 2016

J of Separation Science

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This study aimed to develop and validate a simple and sensitive ultra high performance liquid chromatography tandem mass spectrometry method for the simultaneous determination of sophoraflavanone G and kurarinone in rat plasma by using rutin as the internal standard. Then, the developed method was applied to investigate the pharmacokinetics of sophoraflavanone G and kurarinone in rats after dosing the flavonoid extract from Sophora flavescens. Plasma samples were processed using a liquid-liquid extraction procedure with ethyl acetate. The analysis was performed on a triple quadrupole tandem mass spectrometer by multiple reaction monitoring with an electrospray ionization source in negative ionization mode. Quantitative ion transitions of m/z 423.2→161.2, 437.2→161.1, and 609.3→300.3 were monitored for sophoraflavanone G, kurarinone, and rutin, respectively. The calibration curves of the two analytes exhibited good linearity (r >0.9923) over the range of 0.1-200 ng/mL for sophoraflavanone G and 0.1-1000 ng/mL for kurarinone. Relative standard deviations were less than 13.2% for the intra- and inter-day precisions and no more than 12.6% for the recovery, showing good precision and satisfactory accuracy of the developed method. The validated method was successfully applied to the pharmacokinetic study of sophoraflavanone G and kurarinone after a single intravenous (25 mg/kg) and oral (500 mg/kg) administration of the flavonoid extract from S. flavescens, and the absolute bioavailability for sophoraflavanone G and kurarinone was about 36 and 17%, respectively.

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Section: Introductionmentioning

confidence: 99%

Determination of sophoraflavanone G and kurarinone in rat plasma by UHPLC–MS/MS and its application to a pharmacokinetic study

Yang

Zhang

et al. 2016

J of Separation Science

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“…Owing to very small amounts of M2-M7 being formed, only the major metabolite M1 was prepared using a preparative HPLC, and quantitatively determined using the calibration curve. The hill coefficient (h) was 1.48, indicating that a positive cooperative reaction had occurred between irisflorentin and RLMs (Chen et al, 2014). The regression equation was y = 0.0173x + 0.0053 and the correlation coefficient (r 2 ) was 0.9974.…”

Section: Kinetics Of Irisflorentin Metabolism By Rlmsmentioning

confidence: 96%

“…9, inset) (Moreira et al, 2013;Marques et al, 2014). The hill coefficient (h) was 1.48, indicating that a positive cooperative reaction had occurred between irisflorentin and RLMs (Chen et al, 2014). Those two particular types of rate substrate concentration curves, sigmoidal and convex, were characteristic that the metabolism of irisflorentin was atypical Michaelis-Menten kinetics (Houston and Galetin, 2003).…”

Section: Kinetics Of Irisflorentin Metabolism By Rlmsmentioning

confidence: 97%

Characterization of in vitro metabolites of irisflorentin by rat liver microsomes using high‐performance liquid chromatography coupled with tandem mass spectrometry

Jia

Zeng

Shi

et al. 2016

Biomedical Chromatography

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Belamcanda chinensis has been extensively used as antibechic, expectorant and anti-inflammatory agent in traditional medicine. Irisflorentin is one of the major active ingredients. However, little is known about the metabolism of irisflorentin so far. In this work, rat liver microsomes (RLMs) were used to investigate the metabolism of this compound for the first time. Seven metabolites were detected. Five of them were identified as 6,7-dihydroxy-5,3',4',5'-tetramethoxy isoflavone (M1), irigenin (M2), 5,7,4'-trihydroxy-6,3',5'-trimethoxy isoflavone (M3), 6,7,4'-trihydroxy-5,3',5'-trimethoxy isoflavone (M4) and 6,7,5'-trihydroxy-5,3',4'-trimethoxy isoflavone (M5) by means of NMR and/or HPLC-ESI-MS. The structures of M6 and M7 were not elucidated because they produced no MS signals. The predominant metabolite M1 was noted to be a new compound. Interestingly, it was found to possess anticancer activity much higher than the parent compound. The enzymatic kinetic parameters of M1 revealed a sigmoidal profile, with Vmax = 12.02 μm/mg protein/min, Km = 37.24 μm, CLint = 0.32 μL/mg protein/min and h = 1.48, indicating the positive cooperation. For the first time in this work, a new metabolite of irisflorentin was found to demonstrate a much higher biological activity than its parent compound, suggesting a new avenue for the development of drugs from B. chinensis, which was also applicable for other herbal plants. Copyright © 2016 John Wiley & Sons, Ltd.

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“…Metabolism is an important pharmacokinetic process that influences the biological activity and toxicity of drugs in vivo (13). Certain components of a drug can be converted to toxic metabolites, while other components are transformed to non-toxic metabolites (14). It has been reported that when taken orally, the majority of OMT is transformed into the more absorbable metabolite MT by intestinal bacteria in the gastrointestinal tract (15).…”

Section: Introductionmentioning

confidence: 99%

Oxymatrine and its metabolite matrine contribute to the hepatotoxicity induced by radix Sophorae�tonkinensis in mice

Sun

et al. 2019

Exp Ther Med

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Previous studies by our group demonstrated that radix Sophorae tonkinensis could induce hepatotoxicity. However, it remains unclear which components of this herb may be responsible for its hepatotoxicity. The present study aimed to investigate the hepatic toxicity of treatment with matrine (MT) and oxymatrine (OMT) alone or simultaneously. Furthermore, the current study aimed to identify whether the hepatotoxicity induced by OMT is actually the toxic characterization of its metabolite MT. Hepatotoxicity was evaluated by biochemical and histopathological approaches in subchronic toxicity in mice, as well as via evaluation of cytotoxicity and enzyme leakage in AML12 liver cells. The results indicated that treatment of mice with OMT and MT individually or simultaneously resulted in centrilobular hypertrophy in the liver at doses equivalent to that contained in radix S. tonkinensis at a hepatotoxic dose, suggesting that MT and OMT are likely hepatotoxic components of this herb. OMT-induced hepatotoxicity may be primarily exerted via its metabolite MT in mice. Furthermore, OMT combined with MT was observed to be more toxic compared with OMT or MT alone. These results extend our understanding of the hepatotoxicity of radix S. tonkinensis and its active ingredients.

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Metabolism of the Hepatotoxic Compound Sophoraflavanone G in Rat Liver Microsomes

Cited by 6 publications

References 33 publications

Determination of sophoraflavanone G and kurarinone in rat plasma by UHPLC–MS/MS and its application to a pharmacokinetic study

Determination of sophoraflavanone G and kurarinone in rat plasma by UHPLC–MS/MS and its application to a pharmacokinetic study

Characterization of in vitro metabolites of irisflorentin by rat liver microsomes using high‐performance liquid chromatography coupled with tandem mass spectrometry

Oxymatrine and its metabolite matrine contribute to the hepatotoxicity induced by radix Sophorae�tonkinensis in mice

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