Review articleHerbal hepatotoxicity by kava: Update on pipermethystine, flavokavain B, and mould hepatotoxins as primarily assumed culprits
Introduction
Initial uncertainty prevailed when in Europe cases of hepatotoxicity in temporal association with the use of acetonic and ethanolic extracts from the rhizomes of the anxiolytic herb kava (Piper methysticum Forst. f.) emerged [1], [2]. These cases were perceived unexpected in view of the long tradition of safe kava use in the South Pacific Islands since some thousand years. Previously, the cases of assumed kava hepatotoxicity have been submitted to an ad hoc evaluation procedure with respect to causality for kava that was heavily debated [3], [4], [5], [6], considering also that the assessment method employed for this analysis lacks liver specificity and accuracy [7]. The application of more sophisticated assessment tools with their structured, quantitative, and liver specific characteristics established causality for kava in a few patients with signs of toxic liver injury [8], [9], [10], [11], and additional clinical aspects became evident [8], [11]. In the past, there was speculation about kava hepatotoxicity not only regarding possible culprits [2], [12], [13], [14] but also about both the predictable, intrinsic and the unpredictable, idiosyncratic typologies [1], [8], requiring an update of new developments in the area of this special and exciting field of herbal hepatotoxicity.
In this review, we describe possible new culprits and the typology of kava hepatotoxicity that are at present under consideration and discussion, with the focus on the most recent and relevant causative agents. Amongst these are preferentially pipermethystine, flavokavain B, and mould hepatotoxins.
Section snippets
Kava function and metabolism
Rhizome and root extracts of kava exert psychoactive properties with special reference to anxiolysis, sedation, and relaxation [15]. These psychotropic effects are achieved from modulation of GABA activity via alteration of lipid membrane structure and sodium channel function, monoamine oxidase B inhibition, and noradrenaline and dopamine reuptake inhibition in the brain. Virtually all of the pharmacological activities can be attributed to the presence of six kavalactones as are kavain,
Typology of kava hepatotoxicity
In cases of liver injury induced by conventional synthetic drugs, the classification of the prevailing type of injury is fairly well established [16], [17], [18]. Assignment is made either to the predictable, intrinsic, and dose dependent form that requires an overdose treatment regimen, is therefore rare under the commonly prescribed synthetic drugs, and typically represents the type found for instance in cases of paracetamol overdose; or to the unpredictable, idiosyncratic, and dose
General considerations of possible culprits
In the past, a wealth of possible culprits for kava hepatotoxicity was under consideration and discussion [3], [4], [5], [6], [12], [13], [14], [33]. Amongst these were areas such as ethnic origin prone to liver injury predisposition; hepatic glutathione depletion; cyclooxygenase inhibition; P-glycoprotein alterations; genetic enzyme deficiencies; interactions at the level of hepatic microsomal cytochrome P450 between kavalactones, drugs, and alcohol; comedication; non-compliance of regulatory
Pipermethystine
Within the past few years, there was considerable interest in pipermethystine as a possible culprit of kava hepatotoxicity [14], [34], [35], [36], [37], [38], [39], [40], [41], [42]. The piperidine alkaloid pipermethystine, one of the non-kavalactones present in the kava plant, induces in vitro liver cell death via GSH depletion and modulation of MAPK and NF-κB signalling pathways [37]. These and other in vitro studies have all been carried out with human hepatoma HepG2 cells [37], [40] and
Flavokavain B
The chalcone flavokavain B is a well established constituent of the kava plant [14], [23], [24], [25], [28], [43], [44] and belongs to the group of flavonoids with primarily hepatoprotective properties due to its radical scavenging actions [28], [45]. As a non-kavalactone ingredient present in kava extracts, however, flavokavain B has been considered as a possible culprit for human kava hepatotoxicity [43], [44]. In vitro studies have shown that flavokavain B as a constituent of methanolic
Mould hepatotoxins
Early concerns focused on the possibility that kava raw material could have partially been contaminated by oil, fertilizers, pesticides, nematodes, bacteria, fungi, and specific plant diseases such as kava dieback [38]. However, in the past virtually none of these possible causes has explicitly been evaluated in detail [14], [23]. Recent considerations centre now on the question as to whether kava hepatotoxicity might have been caused by the use of mould kava raw material [25].
The major
Kava plant as raw material
The kava plants exist in form of multiple varieties called cultivars [53], [54], [55], [56], [57], [58] which have been used in the past to prepare kava extracts [12], [13], [23], [38]. To ensure uniformity of the kava raw material as basis for kava extracts, proposals have been made for clinical trials [31], [32], [59], [60] and consumption as herbal dietary supplements [25], [29], [30], [31], [32]. These include the recommendation to prepare water based extracts from peeled roots and rhizomes
Concluding remarks
Kava hepatotoxicity represents primarily a rare herbal idiosyncratic liver injury of the metabolic form, but an additional intrinsic type due to aflatoxins or other hepatotoxins contaminating kava plants after harvest remains to be established. Despite vigorous research efforts, there is little evidence that in vitro cytotoxic compounds such as pipermethystine or flavokavain B may have caused human kava hepatotoxicity. Further research is necessary to evaluate as to whether kava hepatotoxicity
Conflicts of interest statement
No conflicts of interest exist.
References (61)
- et al.
Kava extracts: safety and risks including rare hepatotoxicity
Phytomedicine
(2003) - et al.
Toxicity of kava pyrones, drug safety and precautions – a case study
Phytomedicine
(2003) - et al.
Kava hepatotoxicity: regulatory data selection and causality assessment
Dig Liver Dis
(2009) Kava hepatotoxicity – a clinical review
Ann Hepatol
(2010)- et al.
Severe hepatotoxicity by Indian Ayurvedic herbal products: a structured causality assessment
Ann Hepatol
(2009) - et al.
Kava feeding in rats does not cause liver injury nor enhance galactosamine-induced hepatitis
Food Chem Toxicol
(2007) - et al.
Kava hepatotoxicity solution: a six-point plan for new kava standardization
Phytomedicine
(2011) - et al.
Kava hepatotoxicity: comparison of aqueous, ethanolic, acetonic kava extracts and kava-herbs mixtures
J Ethnopharmacol
(2009) - et al.
Piperidine alkaloids from Piper methysticum
Phytochem
(2003) Kava: an overview
J Ethnopharmacol
(1992)