Insight on toxicity mechanisms of Datura metel L. seeds: a 28-day repeated dose study, in-silico studies, and effect of Shodhana a traditional detoxification method.

Datura metel L., a poisonous medicinal plant is used safely after Shodhana in Ayurveda. It is listed in Schedule E1 of Drugs and Cosmetics Act, as a poisonous medicinal plant to be used with caution. Although known for its toxic effects and reduction of toxicity by Shodhana. However, the toxicity mechanism, effect of Shodhana, and toxicity profile after repeated dosing are missing. Shodhita and Ashodhita Datura metel seeds were subjected to extraction using 70% ethanol and phytochemicals analyzed by LC-MS. Acute and 28-day repeated-dose toxicity studies were conducted as per OECD 423 and OECD 407. Network pharmacology, molecular docking, and dynamics were used to predict the potential multicomponent multitarget interactions and toxicity mechanisms. Ashodhita D. metel exhibited toxicity viz., neurotoxicity and hepatotoxicity, characterized by weight loss, altered organ weights, disrupted hematological, biochemical, behavioral and histological abnormalities. On the contrary, Shodhita D. metel was found safe with NOAEL 100 mg/kg. Whereas it was found to be 25 mg/kg for Ashodhita D. metel. Atropine and Scopolamine are predicted to disrupt cholinergic function and cause inflammation mediated through NFK-β1 and MAPK-1, altering neurotrophin, cAMP, PI3K-AKT, NOD-like receptor, AGE-RAGE, and IL-17 pathways. Atropine and scopolamine major toxic chemicals of D. metel were predicted to disrupt cholinergic function and induce inflammation, potentially mediated through NFK-β1 and MAPK-1 pathways. The Shodhana purification process was found to be effective in mitigating toxicity.