Ying-Jie Chen1, Tse-Yu Chung1, Wen-Ying Chen2, Chung-Yu Chen3, Maw-Rong Lee3, Tzyy-Rong Jinn4, Jason Tc Tzen5. 1. Graduate Institute of Biotechnology, National Chung Hsing University, Taichung 40227, Taiwan, China. 2. Department of Veterinary Medicine, National Chung Hsing University, Taichung 40227, Taiwan, China. 3. Department of Chemistry, National Chung Hsing University, Taichung 40227, Taiwan, China. 4. School of Chinese Medicine, China Medical University, Taichung 40402, Taiwan, China. 5. 1] Graduate Institute of Biotechnology, National Chung Hsing University, Taichung 40227, Taiwan, China [2] School of Chinese Medicine, China Medical University, Taichung 40402, Taiwan, China [3] Agricultural Biotechnology Research Center, Academia Sinica, Taipei 11529, Taiwan, China.
Abstract
AIM: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
AIM: 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. METHODS: 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. RESULTS: 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. CONCLUSION: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.