Insights into sanguinarine toxicity in Rats: Integrating toxicokinetics, oxidative stress, and gut microbial alterations.

Sanguinarine (SAN), a bioactive benzophenanthridine alkaloid derived from Macleaya cordata, has gained attention as a plant-based pesticide and veterinary therapeutic. However, its toxicity mechanisms, particularly concerning toxicokinetics (TK) and gut microbiota interactions, remain poorly understood. This research assessed the acute and subacute toxicity, toxicokinetics, oxidative stress reactions, and changes in gut microbiota associated with SAN in Sprague-Dawley rats. A single oral dose by gavage resulted in a LD50 of 1000 mg/kg·bw (male) and 926 mg/kg·bw (female), classifying SAN under GHS Category 4. Subacute exposure (14 days at 1/10, 1/50, and 1/100 LD50) induced multi-organ damage, including pulmonary haemorrhage, hepatic steatosis, and renal tubular necrosis, with females exhibiting relatively higher sensitivity. Surviving rats recovered from toxic damage during the 14-day recovery period. Toxicokinetic analysis demonstrated dose-dependent plasma concentration curves, nonlinear elimination kinetics, and tissue accumulation in the liver and kidneys. Assays measuring oxidative stress showed unexpected rises in overall antioxidant capacity alongside marked inhibition of glutathione peroxidase, indicating targeted redox disruption. Gut microbiota sequencing identified dose-dependent dysbiosis: high-dose SAN reduced Firmicutes/Bacteroidetes ratios, depleted Lactobacillus, and enriched opportunistic pathogens (Klebsiella, Streptococcus), alongside altered short-chain fatty acid (SCFA) profiles. These findings underscore SAN's potential to induce systemic toxicity through oxidative stress, metabolic disruption, and gut microbiome-mediated inflammation. The LOEAL observed in this study for subacute exposure (14 days) to SAN was 10 mg/kg and the safe use of SAN should be emphasized.