Flavokawains A and B in Kava, Not Dihydromethysticin, Potentiate Acetaminophen-Induced Hepatotoxicity in C57BL/6 Mice

Abstract

Anxiolytic kava products have been associated with rare but severe hepatotoxicity in humans. This adverse potential has never been captured in animal models, and the responsible compound(s) remains to be determined. The lack of such knowledge greatly hinders the preparation of a safer kava product and limits its beneficial applications. In this study we evaluated the toxicity of kava as a single entity or in combination with acetaminophen (APAP) in C57BL/6 mice. Kava alone revealed no adverse effects for long-term usage even at a dose of 500 mg/kg bodyweight. On the contrary a three-day kava pretreatment potentiated APAP-induced hepatotoxicity, resulted in an increase in serum ALT and AST, and increased severity of liver lesions. Chalcone-based flavokawains A (FKA) and B (FKB) in kava recapitulated its hepatotoxic synergism with APAP while dihydromethysticin (DHM, a representative kavalactone and a potential lung cancer chemopreventive agent) had no such effect. These results, for the first time, demonstrate the hepatotoxic risk of kava and its chalcone-based FKA and FKB in vivo and suggest that herb–drug interaction may account for the rare hepatotoxicity associated with anxiolytic kava usage in humans.

Gene expression signatures associated with suppression of TRAMP prostate carcinogenesis by a kavalactone‐rich Kava fraction

“…The alleged safety issues might have resulted from inappropriate causality-assessment approaches [27], improper preparation of Kava raw material [28], and fragmented regulatory standards of agencies and manufacturers [29]. Indeed, Xing lab has documented that flavokavains (absent in KFB), but not kavalactones (enriched in KFB), exhibit synthetic hepatotoxicity with the pain killer drug acetoaminophen (Tylenol) in mice [30]. In summary, KFB diet consumption suppressed the growth of TRAMP epithelial lesions and modified a spectrum of genes in the TRAMP DLP on the one hand, and decreased the incidence of NECa on the other.…”

Chalcone: A Privileged Structure in Medicinal Chemistry

“…Recently, Xing et al found a hepatotoxic risk for one type of chalcone, which needs to be more thoroughly investigated. 252 Flavokawains A ( 58 ) and B ( 59 ) (Figure 4), two chalcone derivatives isolated from kava kava, a natural source of great human health relevance, exhibit hepatotoxic synergism with aceta6minophen, demonstrating and characterizing the hepatotoxic risk of kava. Another study reported that flavokawain A could significantly inhibit cytochrome P450 isotypes (CYP1A2,CYP2D1,CYP2C6, and CYP3A2), providing the mechanistic insights of the hepatic adverse side effect of flavokawain A and kava extracts.…”

Flavokawains A and B from kava (Piper methysticum) activate heat shock and antioxidant responses and protect against hydrogen peroxide-induced cell death in HepG2 hepatocytes

“…Notably, flavokawains A and B (FKA, FKB) have demonstrated anticancer activity in preclinical experiments, including murine models of breast, bladder and prostate cancer (Abu et al, 2015; Tang et al, 2010; Zi & Simoneau, 2005). But while FKA and FKB are orally active in mice, they are also suspected to either cause or potentiate liver damage by other agents including ethanol or acetaminophen (Li & Ramzan, 2010; Narayanapillai et al, 2014). For this reason, we have sought to better understand the relative toxicities of FKA and FKB in human liver cells and evaluate their effects on intracellular signaling related to hepatocyte viability.…”