Chen Ying-Jie, Chung Tse-Yu, Chen Wen-Ying, Chen Chung-Yu, Lee Maw-Rong, Jinn Tzyy-Rong, Tc Tzen Jason
Graduate Institute of Biotechnology, National Chung Hsing University, Taichung 40227, Taiwan, China.
Department of Veterinary Medicine, National Chung Hsing University, Taichung 40227, Taiwan, China.
Acta Pharmacol Sin. 2014 Jul;35(7):937-44. doi: 10.1038/aps.2014.37.
Lithospermate B (LSB) isolated from the traditional Chinese medicine danshen (Salvia miltiorrhiza) is an effective Na(+)/K(+)-ATPase inhibitor and used to treat congestive heart failure. The inhibition of LSB on Na(+)/K(+)-ATPase is potentiated by forming complexes with transition metal ions. Here we investigated the safety and metabolites of different transition metal-LSB complexes in rats.
LSB complexed with six different transition metal ions (Mg(2+), Zn(2+), Cr(3+), Co(2+), Ni(2+) and Mn(2+)) were prepared. Adult male SD rats were injected with the different metal-LSB complexes (50 mg/kg, iv), and their bile and blood samples were collected. The metabolites of the metal-LSB complexes in the samples were analyzed using mass spectroscopy.
In rats injected with LSB complexed with Mg(2+), Zn(2+), Cr(3+), Ni(2+) or Mn(2+), LSB and its four putative metabolites were equivalently detected in their bile samples. Mn(2+)-LSB exhibited distinct metabolite profiles compared with the other four metal-LSB complexes. The four putative metabolites were identified as 3-monomethyl-LSB, 3,3''-dimethyl-LSB, 3,3'''-dimethyl-LSB and 3,3'',3'''-trimethyl-LSB. The tracking of successive bile samples of rats injected with Mg(2+)-LSB, Zn(2+)-LSB and Mn(2+)-LSB concurrently demonstrated that LSB was firstly methylated at position 3, then at position 3'', and, finally, the 3''' hydroxyl group. All rats injected with Co(2+)-LSB died.
Zn(2+)-LSB, Cr(3+)-LSB, Ni(2+)-LSB or Mn(2+)-LSB produces identical four methylated metabolites of LSB in rats, and seemed to be as safe as LSB or Mg(2+)-LSB.
从中药丹参（Salvia miltiorrhiza）中分离得到的紫草酸B（LSB）是一种有效的钠钾ATP酶抑制剂，可用于治疗充血性心力衰竭。LSB与过渡金属离子形成复合物后，对钠钾ATP酶的抑制作用会增强。在此，我们研究了不同过渡金属-LSB复合物在大鼠体内的安全性和代谢产物。
制备了与六种不同过渡金属离子（Mg(2+)、Zn(2+)、Cr(3+)、Co(2+)、Ni(2+)和Mn(2+)）络合的LSB。成年雄性SD大鼠静脉注射不同的金属-LSB复合物（50 mg/kg），并采集其胆汁和血液样本。使用质谱分析样本中金属-LSB复合物的代谢产物。
在注射了与Mg(2+)、Zn(2+)、Cr(3+)、Ni(2+)或Mn(2+)络合的LSB的大鼠中，在其胆汁样本中同等程度地检测到了LSB及其四种推定代谢产物。与其他四种金属-LSB复合物相比，Mn(2+)-LSB表现出不同的代谢产物谱。这四种推定代谢产物被鉴定为3-单甲基-LSB、3,3''-二甲基-LSB、3,3'''-二甲基-LSB和3,3'',3'''-三甲基-LSB。同时对注射了Mg(2+)-LSB、Zn(2+)-LSB和Mn(2+)-LSB的大鼠的连续胆汁样本进行追踪表明，LSB首先在3位甲基化，然后在3''位甲基化，最后在3'''位羟基甲基化。所有注射Co(2+)-LSB的大鼠均死亡。
Zn(2+)-LSB、Cr(3+)-LSB、Ni(2+)-LSB或Mn(2+)-LSB在大鼠体内产生与LSB相同的四种甲基化代谢产物，并且似乎与LSB或Mg(2+)-LSB一样安全。
