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The safety assessment of cinnabar: Effects of co-administration with selenium on renal toxicity in mice

Ziyan Han,Yuzhou Zhuo,Zhihui Dai,Xinhui Zhang,Bingqian Zhu,Yuyan Liu,Zhuoyu Chai,Jiayi Wu,Lijun Chen

Background Cinnabar is a mercury-containing mineral traditionally used in Chinese medicine and can induce kidney injury via mercury toxicity. Given that cinnabar contains elements such as selenium, it is reasonable to hypothesize that its multi-element composition may regulate nephrotoxicity through intermetallic interactions. To validate this hypothesis and clarify the distinct renal toxicity between cinnabar and single mercury compounds, we compared the nephrotoxic effects of cinnabar, Zhu-Sha-An-Shen-Wan (ZSASW), mercuric sulfide (HgS), and mercuric nitrate (Hg(NO₃)₂). By co-administration with sodium selenite (Na₂SeO₃), this study related to the nephrotoxicity of cinnabar was improved from the perspective of metal-element interactions, which provided a new perspective for the safety assessment of mercury-containing medicines. Methods Mice were gavaged with 0.5 % CMC-Na solution, cinnabar (50.0 and 200 mg/kg), HgS (50.0 mg/kg), Na 2 SeO 3 (1.00 mg/kg), cinnabar (50.0 mg/kg)+Na 2 SeO 3 (1.00 mg/kg), HgS (50.0 mg/kg)+Na 2 SeO 3 (1.00 mg/kg), ZSASW (600 mg/kg), ZSASW (600 mg/kg)+Na 2 SeO 3 (1.00 mg/kg) or Hg(NO 3 ) 2 (0.900 mg/kg in Hg 2+ ) daily for 30 days. Renal histopathology was assessed by H&E staining. Related protein expression was measured by Western blotting. Renal total Hg (THg) concentration in kidney was determined by cold vapor atomic fluorescence spectroscopy. Result Western blotting revealed significantly decreased OAT1 and GPX4 levels in all experimental groups compared to the Control group ( P  < 0.05). NF-κB activation occurred in the Hg(NO₃)₂, Cinnabar-H, HgS, and HgS-Na₂SeO₃ groups. Hg(NO₃)₂ administration caused a significant decline in body weight growth rate ( P  < 0.001), severe renal tubular degeneration with epithelial cell swelling, and the highest renal THg concentration (773.77 % exceeding the Control group). Na₂SeO₃ alone induced inflammatory infiltration and tubular epithelial degeneration. The Cinnabar-H and HgS groups exhibited distinct renal damage (localized tubular degeneration and vascular hyaline degeneration, respectively) with elevated renal THg concentration (330.74 % and 347.95 % exceeding the Control group). The Cinnabar-L, Cinnabar-Na₂SeO₃, ZSASW, and ZSASW-Na₂SeO₃ groups maintained normal histology despite increased renal mercury content (227.46 %, 40.57 %, 67.2 %, and 556.56 % exceeding the Control group). Co-administration of Na₂SeO₃ with HgS restored OAT1 and GPX4 expression ( P  < 0.001), suppressed NF-κB activation, and minimally altered renal mercury accumulation (RSD=0.45 %). Na₂SeO₃ reduced mercury levels in the cinnabar-treated mice (57.07 % reduction) but increased accumulation in ZSASW-treated mice (292.65 % increase). Conclusion This study confirms that cinnabar and ZSASW exhibit lower toxicity than mercuric sulfide or mercuric nitrate. Multi-component synergistic or antagonistic effects need to be considered when studying the mechanism of action of cinnabar-related drugs.