a College of Pharmacy , Chengdu University of Traditional Chinese Medicine , Chengdu , P.R. China.
b Pharmaceutical Department , The Second Affiliated Hospital of Hainan Medical University , Haikou , P.R. China.
Pharm Biol. 2018 Dec;56(1):678-690. doi: 10.1080/13880209.2018.1543332.
Tsothel, a traditional Tibetan medicine, is regarded as 'the king of essences'. Nevertheless, tsothel has aroused serious concern regarding its biosafety because its main component is HgS. Unfortunately, toxicological studies on tsothel are scarce.
As inorganic mercury has high affinity for the kidney, the present investigation was designed to determine the potential nephrotoxicity and mechanism of tsothel.
Sprague-Dawley rats were orally administered different doses of tsothel (0, 66.70, 33.35 and 16.68 mg/kg) daily for 180 days, followed by the withdrawal of tsothel for 120 days. Then, the related nephrotoxicity was examined by the ICP-MS, ELISA, colorimetric, RT-PCR, HE staining, immunohistochemical staining and flow cytometry methods.
Although tsothel administration led to a large accumulation of Hg (794.25 ± 464.30 ng/g in the 66.70 mg/kg group, 775.75 ± 307.89 ng/g in the 33.35 mg/kg group and 532.60 ± 356.77 ng/g in the 16.68 mg/kg group) in the kidney after 120 days of tsothel withdrawal, the blood CREA and BUN, urinary Kim-1, NAG, RBP and β2-MG, renal SOD, MDA, pathology, proliferation, apoptosis and cell cycle had no significant changes compared with the control group. Additionally, the high GSH content (318.87 ± 44.19 nmol/mL in the 33.35 mg/kg group) and the relative expression levels of Kim-1 (1.08 ± 0.11 in the 33.35 mg/kg group), MT-1 (1.46 ± 0.10 in the 66.70 mg/kg group, 1.61 ± 0.19 in the 33.35 mg/kg group and 1.57 ± 0.14 in the 16.68 mg/kg group) and GST-Pi (1.76 ± 0.89 in the 33.35 mg/kg group) mRNA recovered to normal after tsothel withdrawal. Interestingly, the change trend of GST-Pi gene expression was consistent with the change trend of GSH activity.
Overall, our study shows that tsothel administration did not induce overt nephrotoxicity but did have reversible stress-related effects. These results suggest that tsothel affects stress response mechanisms with the involvement of detoxifying enzyme systems. The formulation method and chemotype could play a role in the reduced toxicity potential of tsothel compared to common mercurials.
藏药“佐太”被视为“众药之王”，但其主要成分硫化汞（HgS）引发了人们对其生物安全性的严重担忧。然而，有关“佐太”的毒理学研究却很少。
由于无机汞对肾脏具有高亲和力，本研究旨在确定“佐太”潜在的肾毒性及其机制。
Sprague-Dawley 大鼠每天经口给予不同剂量的“佐太”（0、66.70、33.35 和 16.68mg/kg），持续 180 天，然后停止给予“佐太”120 天。然后，采用 ICP-MS、ELISA、比色法、RT-PCR、HE 染色、免疫组化染色和流式细胞术方法检测相关的肾毒性。
尽管在停止给予“佐太”120 天后，大鼠肾脏中 Hg 的蓄积量很大（66.70mg/kg 组为 794.25±464.30ng/g，33.35mg/kg 组为 775.75±307.89ng/g，16.68mg/kg 组为 532.60±356.77ng/g），但血 CREA 和 BUN、尿 Kim-1、NAG、RBP 和β2-MG、肾 SOD、MDA、病理变化、细胞增殖、细胞凋亡和细胞周期与对照组相比无明显变化。此外，高 GSH 含量（33.35mg/kg 组为 318.87±44.19nmol/mL）和 Kim-1（33.35mg/kg 组为 1.08±0.11）、MT-1（66.70mg/kg 组为 1.46±0.10，33.35mg/kg 组为 1.61±0.19，16.68mg/kg 组为 1.57±0.14）和 GST-Pi（33.35mg/kg 组为 1.76±0.89）mRNA 的相对表达水平恢复正常。有趣的是，GST-Pi 基因表达的变化趋势与 GSH 活性的变化趋势一致。
总的来说，本研究表明“佐太”给药并未引起明显的肾毒性，但确实存在与应激相关的可逆作用。这些结果表明，“佐太”通过参与解毒酶系统影响应激反应机制。与常见的汞化合物相比，“佐太”的配方方法和化学类型可能发挥了降低毒性潜力的作用。
