AUTHOR=Balkrishna Acharya , Sakat Sachin Shridhar , Ranjan Ravikant , Joshi Kheemraj , Shukla Sunil , Joshi Kamal , Verma Sudeep , Gupta Abhishek , Bhattacharya Kunal , Varshney Anurag 

TITLE=Polyherbal Medicine Divya Sarva-Kalp-Kwath Ameliorates Persistent Carbon Tetrachloride Induced Biochemical and Pathological Liver Impairments in Wistar Rats and in HepG2 Cells

JOURNAL=Frontiers in Pharmacology

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2020.00288

DOI=10.3389/fphar.2020.00288

ISSN=1663-9812

ABSTRACT=<p>Divya Sarva-Kalp-Kwath (SKK) is a poly-herbal ayurvedic medicine formulated using plant extracts of <italic>Boerhavia diffusa</italic> L. (Nyctaginaceae), <italic>Phyllanthus niruri</italic> L. (Euphorbiaceae), and <italic>Solanum nigrum</italic> L. (Solanaceae), described to improve liver function and general health. In the present study, we have explored the hepatoprotective effects of SKK in ameliorating carbon tetrachloride (CCl<sub>4</sub>) induced liver toxicity using <italic>in-vitro</italic> and <italic>in-vivo</italic> test systems. Chemical analysis of SKK using Liquid Chromatography-Mass Spectroscopy (LC-MS-QToF) and High-Performance Liquid Chromatography (HPLC) revealed the presence of different bioactive plant metabolites, known to impart hepatoprotective effects. In human hepatocarcinoma (HepG2) cells, co-treatment of SKK with CCl<sub>4</sub> effectively reduced the hepatotoxicity induced by the latter. These effects were confirmed by studying parameters such as loss of cell viability; release of hepatic injury enzymatic biomarkers- aspartate aminotransferase (AST), and alkaline phosphatase (ALP); and changes in reactive oxygen species and in mitochondrial membrane potentials. <italic>In-vivo</italic> safety analysis in Wistar rats showed no loss in animal body weight, or change in feeding habits after repeated oral dosing of SKK up to 1,000 mg/kg/day for 28 days. Also, no injury-related histopathological changes were observed in the animal's blood, liver, kidney, heart, brain, and lung. Pharmacologically, SKK played a significant role in modulating CCl<sub>4</sub> induced hepatic injuries in the Wistar rats at a higher dose. In the 9 weeks' study, SKK (200 mg/kg) reduced the CCl<sub>4</sub> stimulated increase in the release of enzymes (ALT, AST, and ALP), bilirubin, total cholesterol, and uric acid levels in the Wistar rats. It also reduced the CCl<sub>4</sub> stimulated inflammatory lesions such as liver fibrosis, lymphocytic infiltration, and hyper-plasticity. In conclusion, SKK showed pharmacological effects in improving the CCl<sub>4</sub> stimulated liver injuries in HepG2 cells and in Wistar rats. Furthermore, no adverse effects were observed up to 10× higher human equivalent dose of SKK during 28-days repeated dose exposure in Wistar rats. Based on the literature search on the identified plant metabolites, SKK was found to act in multiple ways to ameliorate CCl<sub>4</sub> induced hepatotoxicity. Therefore, polyherbal SKK medicine has shown remarkable potentials as a possible alternative therapeutics for reducing liver toxicity induced by drugs, and other toxins.</p>