Biotransformation of Flavokawains A, B, and C, Chalcones from Kava (<i>Piper methysticum</i>), by Human Liver Microsomes

Zenger, Katharina; Agnolet, Sara; Schneider, Bernd; Kraus, Birgit

doi:10.1021/acs.jafc.5b01858

Cited by 22 publications

(13 citation statements)

References 35 publications

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“…The impact of quinoid metabolites could be relevant, and therefore contribute to hepatotoxicity in vivo , in case of saturation of conjugation pathways or for the alteration of metabolic routes. Other authors [ 149 ], after examining the in vitro metabolism of flavokawains, highlight that the chalcone metabolite conjugates could presumably be active in vivo , and that currently these metabolites are not included in routine testing.…”

Section: Resultsmentioning

confidence: 99%

Hepatotoxicity Induced by “the 3Ks”: Kava, Kratom and Khat

Pantano

Tittarelli

Mannocchi

et al. 2016

IJMS

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The 3Ks (kava, kratom and khat) are herbals that can potentially induce liver injuries. On the one hand, growing controversial data have been reported about the hepatotoxicity of kratom, while, on the other hand, even though kava and khat hepatotoxicity has been investigated, the hepatotoxic effects are still not clear. Chronic recreational use of kratom has been associated with rare instances of acute liver injury. Several studies and case reports have suggested that khat is hepatotoxic, leading to deranged liver enzymes and also histopathological evidence of acute hepatocellular degeneration. Numerous reports of severe hepatotoxicity potentially induced by kava have also been highlighted, both in the USA and Europe. The aim of this review is to focus on the different patterns and the mechanisms of hepatotoxicity induced by “the 3Ks”, while trying to clarify the numerous aspects that still need to be addressed.

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Section: Resultsmentioning

confidence: 99%

Hepatotoxicity Induced by “the 3Ks”: Kava, Kratom and Khat

Pantano

Tittarelli

Mannocchi

et al. 2016

IJMS

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“…There is no data available on the metabolization of DMC in vivo. The compound is likely hydroxylated and glucuronidated, as it is the case for similar compounds such as cardamonin and flavokawains [ 87 , 88 ]. The pharmacokinetic properties of DMC are not known.…”

Section: Discussionmentioning

confidence: 99%

Mechanistic insights into dimethyl cardamonin-mediated pharmacological effects: A double control of the AMPK-HMGB1 signaling axis

Bailly

Vergoten

2020

Life Sciences

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Dimethyl cardamonin (DMC) has been isolated from diverse plants, notably from Cleistocalyx operculatus . We have reviewed the pharmacological properties of this natural product which displays anti-inflammatory, anti-hyperglycemic and anti-cancer properties. The pharmacological activities essentially derive from the capacity of DMC to interact with the protein targets HMGB1 and AMPK. Upon binding to HMGB1, DMC inhibits the nucleocytoplasmic transfer of the protein and its extracellular secretion, thereby blocking its alarmin function. DMC also binds to the AMP site of AMPK to activate phospho-AMPK and then to trigger downstream signals leading to the anti-inflammatory and anti-hyperglycemic effects. AMPK activation by DMC reinforces inhibition of HMGB1, to further reduce the release of the alarmin protein, likely contributing to the anticancer effects. The characterization of a tight control of DMC over the AMPK-HMGB1 axis not only helps to explain the known activities of DMC but also suggests opportunities to use this chalcone to treat other pathological conditions such as the acute respiratory distress syndrome (which affects patients with COVID-19). DMC structural analogues are also evoked.

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“…The chalcone flavokawain was found to exhibit promising anticancer and anti-inflammatory properties in previous studies [39,40]. DiNap, a synthetic analog of the chalcone flavokawain, was evaluated in this study for its potential antiviral activity against PRRSV infection in cell culture systems and in a pig model.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the Inhibitory Effects of (E)-1-(2-hydroxy-4,6-dimethoxyphenyl)-3-(naphthalen-1-yl)prop-2-en-1-one (DiNap), a Natural Product Analog, on the Replication of Type 2 PRRSV In Vitro and In Vivo

et al. 2019

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DiNap [(E)-1-(2-hydroxy-4,6-dimethoxyphenyl)-3-(naphthalen-1-yl)prop-2-en-1-one], an analog of a natural product (the chalcone flavokawain), was synthesized and characterized in this study. Porcine reproductive and respiratory syndrome virus (PRRSV) is the most challenging threat to the swine industry worldwide. Currently, commercially available vaccines are ineffective for controlling porcine reproductive and respiratory syndrome (PRRS) in pigs. Therefore, a pharmacological intervention may represent an alternative control measure for PRRSV infection. Hence, the present study evaluated the effects of DiNap on the replication of VR2332 (a prototype strain of type 2 PRRSV). Initially, in vitro antiviral assays against VR2332 were performed in MARC-145 cells and porcine alveolar macrophages (PAMs). Following this, a pilot study was conducted in a pig model to demonstrate the effects of DiNap following VR2332 infection. DiNap inhibited VR2332 replication in both cell lines in a dose-dependent manner, and viral growth was completely suppressed at concentrations ≥0.06 mM, without significant cytotoxicity. Consistent with these findings, in the pig study, DiNap also reduced viral loads in the serum and lungs and enhanced the weight gain of pigs following VR2332 infection, as indicated by comparison of the DiNap-treated groups to the untreated control (NC) group. In addition, DiNap-treated pigs had fewer gross and microscopic lesions in their lungs than NC pigs. Notably, virus transmission was also delayed by approximately 1 week in uninfected contact pigs within the same group after treatment with DiNap. Taken together, these results suggest that DiNap has potential anti-PRRSV activity and could be useful as a prophylactic or post-exposure treatment drug to control PRRSV infection in pigs.

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Biotransformation of Flavokawains A, B, and C, Chalcones from Kava (Piper methysticum), by Human Liver Microsomes

Cited by 22 publications

References 35 publications

Hepatotoxicity Induced by “the 3Ks”: Kava, Kratom and Khat

Hepatotoxicity Induced by “the 3Ks”: Kava, Kratom and Khat

Mechanistic insights into dimethyl cardamonin-mediated pharmacological effects: A double control of the AMPK-HMGB1 signaling axis

Evaluation of the Inhibitory Effects of (E)-1-(2-hydroxy-4,6-dimethoxyphenyl)-3-(naphthalen-1-yl)prop-2-en-1-one (DiNap), a Natural Product Analog, on the Replication of Type 2 PRRSV In Vitro and In Vivo

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