A stable isotope dilution tandem mass spectrometry method of major kavalactones and its applications

Wang, Yi; Eans, Shainnel O.; Stacy, Heather M.; Narayanapillai, Sreekanth C.; Sharma, Abhisheak; Fujioka, Naomi; Haddad, Linda; McLaughlin, Jay P.; Avery, Bonnie A.; Xing, Chengguo

doi:10.1371/journal.pone.0197940

Cited by 17 publications

(9 citation statements)

References 44 publications

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“…One-week exposure showed no adverse effects [ 112 ]. Kavain, dihydrokavain, methysticin, dihydromethysticin, and desmethoxyyangonin were quantified to account for 33.7%, 18.2%, 10.4%, 27.3% and 10.4%, respectively, of the total kavalactones [ 179 ].…”

Section: Safety Of Kava and Its Hepatotoxic Riskmentioning

confidence: 99%

Kava as a Clinical Nutrient: Promises and Challenges

et al. 2020

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Kava beverages are typically prepared from the root of Piper methysticum. They have been consumed among Pacific Islanders for centuries. Kava extract preparations were once used as herbal drugs to treat anxiety in Europe. Kava is also marketed as a dietary supplement in the U.S. and is gaining popularity as a recreational drink in Western countries. Recent studies suggest that kava and its key phytochemicals have anti-inflammatory and anticancer effects, in addition to the well-documented neurological benefits. While its beneficial effects are widely recognized, rare hepatotoxicity had been associated with use of certain kava preparations, but there are no validations nor consistent mechanisms. Major challenges lie in the diversity of kava products and the lack of standardization, which has produced an unmet need for quality initiatives. This review aims to provide the scientific community and consumers, as well as regulatory agencies, with a broad overview on kava use and its related research. We first provide a historical background for its different uses and then discuss the current state of the research, including its chemical composition, possible mechanisms of action, and its therapeutic potential in treating inflammatory and neurological conditions, as well as cancer. We then discuss the challenges associated with kava use and research, focusing on the need for the detailed characterization of kava components and associated risks such as its reported hepatotoxicity. Lastly, given its growing popularity in clinical and recreational use, we emphasize the urgent need for quality control and quality assurance of kava products, pharmacokinetics, absorption, distribution, metabolism, excretion, and foundational pharmacology. These are essential in order to inform research into the molecular targets, cellular mechanisms, and creative use of early stage human clinical trials for designer kava modalities to inform and guide the design and execution of future randomized placebo controlled trials to maximize kava’s clinical efficacy and to minimize its risks.

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Section: Safety Of Kava and Its Hepatotoxic Riskmentioning

confidence: 99%

Kava as a Clinical Nutrient: Promises and Challenges

et al. 2020

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“…The two methods either had a long run time (50 min) or sacrificed the resolution among some key compounds. The UPLC-MS/MS method [23] was also reported for analysis of KLs, however, the linear range of UPLC-MS/MS was limited.…”

Section: Introductionmentioning

confidence: 99%

A UHPLC-UV Method Development and Validation for Determining Kavalactones and Flavokavains in Piper methysticum (Kava)

Tang¹,

Fields²

2019

Molecules

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An ultra-high-performance liquid chromatographic (UHPLC) separation was developed for six kava pyrones (methysticin, dihydromethysticin (DHM), kavain, dihydrokavain (DHK), desmethoxyyangonin (DMY), and yangonin), two unidentified components, and three Flavokavains (Flavokavain A, B, and C) in Piper methysticum (kava). The six major kavalactones and three flavokavains are completely separated (Rs > 1.5) within 15 min using a HSS T3 column and a mobile phase at 60 °C. All the peaks in the LC chromatogram of kava extract or standard solutions were structurally confirmed by LC-UV-MS/MS. The degradations of yangonin and flavokavains were observed among the method development. The degradation products were identified as cis-isomerization by MS/MS spectra. The isomerization was prevented or limited by sample preparation in a non-alcoholic solvent or with no water. The method uses the six kava pyrones and three flavokavains as external standards. The quantitative calibration curves are linear, covering a range of 0.5–75 μg/mL for the six kava pyrones and 0.05–7.5 μg/mL for the three flavokavains. The quantitation limits for methysticin, DHM, kavain, DHK, DMY, and yangonin are approximately 0.454, 0.480, 0.277, 0.686, 0.189, and 0.422 μg/mL. The limit of quantification (LOQs) of the three flavokavains are about 0.270, 0.062, and 0.303 μg/mL for flavokavain C (FKC), flavokavain A (FKA), and flavokavain B (FKB). The average recoveries at three different levels are 99.0–102.3% for kavalactones (KLs) and 98.1–102.9% for flavokavains (FKs). This study demonstrates that the method of analysis offers convenience and adequate sensitivity for determining methysticin, DHM, kavain, DHK, yangonin, DMY, FKA, FKB, and FKC in kava raw materials (root and CO2 extract) and finished products (dry-filled capsule and tablet).

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“…More importantly, several analogs, structurally similar as DHM, have been discovered with distinct potency in reducing DNA damage, particularly (−)‐DHM and 5 f . Although their pharmacokinetics could be potential variables, we have previously characterized that DHM and dihydrokavain have similar pharmacokinetics, [30] suggesting that pharmacokinetics unlikely accounts for their distinct SARs observed herein. Upon confirming their similar pharmacokinetics in the future, these DHM analogs will be powerful in vivo chemical probes to define DNA damage dependent and independent mechanisms in NNK‐induced lung cancer chemoprevention, which is critical to the basic understanding of NNK‐induced lung carcinogenesis and DHM‐based chemoprevention.…”

Section: Discussionmentioning

confidence: 84%

In vivo Structure‐Activity Relationship of Dihydromethysticin in Reducing Nicotine‐Derived Nitrosamine Ketone (NNK)‐Induced Lung DNA Damage against Lung Carcinogenesis in A/J Mice

Xing

Hati

et al. 2022

ChemMedChem

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Lung cancer is the leading cause of cancer-related deaths and chemoprevention should be developed. We recently identified dihydromethysticin (DHM) as a promising candidate to prevent NNK-induced lung tumorigenesis. To probe its mechanisms and facilitate its future translation, we investigated the structureactivity relationship of DHM on NNK-induced DNA damage in A/J mice. Twenty DHM analogs were designed and synthesized. Their activity in reducing NNK-induced DNA damage in the target lung tissues was evaluated. The unnatural enantiomer of DHM was identified to be more potent than the natural enantiomer. The methylenedioxy functional moiety did not tolerate modifications while the other functional groups (the lactone ring and the ethyl linker) accommodated various modifications. Importantly, analogs of high structural similarity to DHM with distinct efficacy in reducing NNK-induced DNA damage have been identified. They will serve as chemical probes to elucidate the mechanisms of DHM in blocking NNK-induced lung carcinogenesis.

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A stable isotope dilution tandem mass spectrometry method of major kavalactones and its applications

Cited by 17 publications

References 44 publications

Kava as a Clinical Nutrient: Promises and Challenges

Kava as a Clinical Nutrient: Promises and Challenges

A UHPLC-UV Method Development and Validation for Determining Kavalactones and Flavokavains in Piper methysticum (Kava)

In vivo Structure‐Activity Relationship of Dihydromethysticin in Reducing Nicotine‐Derived Nitrosamine Ketone (NNK)‐Induced Lung DNA Damage against Lung Carcinogenesis in A/J Mice

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