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Background. Realgar was usually selected as a substitute for arsenic trioxide to treat acute promyelocytic leukemia due to its higher effect without high cardiotoxicity. In traditional Chinese medicine (TCM), realgar is usually processed by the water-grinding method clinically, but the mechanism of realgar processing detoxification is still unclear. However, it is necessary to take safety and efficacy into account while evaluating a drug. Methods. Sixty male Wistar rats were divided into control group, realgar products-treated groups, and corresponding subgroups. Biochemistry analysis and histopathological examination were performed in the study, and plasma samples were collected from all the rats for metabolomics analysis. Results. No significant toxicity was observed in rats treated with 0.64 g/kg/day grinding realgar (G-r) and water-grinding realgar (WG-r). When the dose increased to 1.92 g/kg/day, the liver weight coefficients of the rats treated with G-r (HG-r: 3.65 ± 0.26%) and WG-r (HWG-r: 3.67 ± 0.14%) increased significantly and severe hepatic injury occurred in comparison to the control group (Group C: 3.00 ± 0.21%). After one week's withdrawal, the liver injury caused by the high dose of WG-r significantly recovered, while the liver damage caused by G-r was more difficult to recover. In metabolomics analysis, 14 metabolites were identified as the potential biomarkers in realgar-treated rats. These metabolites indicated that there were perturbations of the primary bile acid biosynthesis, arachidonic acid metabolism, linoleic acid metabolism, and glycerophospholipid metabolism in the realgar-treated groups. Conclusions. These results illustrate that, as a TCM processing method, water grinding had the effect of reducing toxicity, and the metabolomics method may be a valuable tool for studying the toxicity induced by TCM and the mechanism of TCM processing.

Study on the Mechanism of Reducing Hepatotoxicity of Water-Grinding Realgar by Metabolomics, Morphology, and Chemical Analysis