Acute toxicity of diallyl sulfide derived from Allium sativum (garlic) in mice and its possible mechanisms

Background: Diallyl sulfide (DAS) is a garlic-derived organosulfur compound known for its chemotherapeutic properties, as a strong food additive and a potential radiomitigator. Despite its therapeutic potentials, the apparent lack of toxicity data hinders its clinical applications. Purpose: The present study investigated the pre-clinical toxicity of DAS to identify the maximum tolerable and lethal doses and understand its underlying mechanisms at toxic doses. Study design: DAS was administered intraperitoneally to C57BL/6 mice at a range of concentrations (160, 1280, 1600, and 1920 mg/kg). Standard toxicological endpoints (survival, body weight changes, hematology, histopathology, and serum biochemistry) were supported with genotoxicity and molecular studies. Findings were correlated with DAS stability by HPLC. Results: A single dose of DAS up to 1280 mg/kg was well-tolerated without significant changes in standard toxicological parameters. Death was observed at 1600 mg/kg (1/5 male) and 1920 mg/kg (2/5 female and 3/5 male) doses. DAS at 1920 mg/kg dose level also induced marked pathological changes in the lungs, liver, and reproductive organs. This dose increased hepatic enzyme activities and significantly reduced blood cell count. Inflammatory markers like CD68 and NF-κB were upregulated in the lungs. Propidium iodide stained ovarian and testicular germ cells revealed alterations in cell cycle distribution and increased cell death at 1920 mg/kg dose. At the highest dose of DAS, evidence of genotoxicity in terms of the occurrence of a few double minutes, rings, and fragments appeared. HPLC studies revealed a significant and rapid decrease in the DAS peak area following incubation with canola oil or plasma in vitro. Conclusion: Our results indicated that lungs, liver, and reproductive organs are affected at higher DAS doses. Based on the findings, we conclude that excessive usage of DAS should be limited owing to the associated toxicities at higher concentrations (1600 mg/kg and above)