The integrated use of in silico methods for the hepatotoxicity potential of Piper methysticum

Herbal products as supplements and therapeutic intervention have been used for centuries. However, their toxicities are not completely evaluated and the mechanisms are not clearly understood. Dried rhizome of the plant kava (Piper methysticum) is used for its anxiolytic, and sedative effects. The drug is also known for its hepatotoxicity potential. Major constituents of the plant were identified as kavalactones, alkaloids and chalcones in previous studies. Kava hepatotoxicity mechanism and the constituent that causes the toxicity have been debated for decades. In this paper, we illustrated the use of computational tools for the hepatotoxicity of kava constituents. The proposed mechanisms and major constituents that are most probably responsible for the toxicity have been scrutinized. According to the experimental and prediction results, the kava constituents play a substantial role in hepatotoxicity by some means or other via glutathione depletion, CYP inhibition, reactive metabolite formation, mitochondrial toxicity and cyclooxygenase activity. Some of the constituents, which have not been tested yet, were predicted to involve mitochondrial membrane potential, caspase-3 stimulation, and AhR activity. Since Nrf2 activation could be favorable for prevention of hepatotoxicity, we also suggest that these compounds should undergo testing given that they were predicted not to be activating Nrf2. Among the major constituents, alkaloids appear to be the least studied and the least toxic group in general. The outcomes of the study could help to appreciate the mechanisms and to prioritize the kava constituents for further testing.

Keywords: DILI; Kava; Piper methysticum; Tox21; hepatotoxicity; toxicity prediction.