title: Detecting metabolites of different transition metal-lithospermate B complexes after intravenous injection in rats.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Graduate Institute of Biotechnology, National Chung Hsing University, Taichung 40227, Taiwan, China.
authors.forename: Ying-Jie
authors.initials: YJ
authors.lastname: Chen
authors.affiliation: Graduate Institute of Biotechnology, National Chung Hsing University, Taichung 40227, Taiwan, China.
authors.forename: Tse-Yu
authors.initials: TY
authors.lastname: Chung
authors.affiliation: Department of Veterinary Medicine, National Chung Hsing University, Taichung 40227, Taiwan, China.
authors.forename: Wen-Ying
authors.initials: WY
authors.lastname: Chen
authors.affiliation: Department of Chemistry, National Chung Hsing University, Taichung 40227, Taiwan, China.
authors.forename: Chung-Yu
authors.initials: CY
authors.lastname: Chen
authors.affiliation: Department of Chemistry, National Chung Hsing University, Taichung 40227, Taiwan, China.
authors.forename: Maw-Rong
authors.initials: MR
authors.lastname: Lee
authors.affiliation: School of Chinese Medicine, China Medical University, Taichung 40402, Taiwan, China.
authors.forename: Tzyy-Rong
authors.initials: TR
authors.lastname: Jinn
authors.affiliation: 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.
authors.forename: Jason
authors.initials: J
authors.lastname: Tc Tzen
mesh_terms: D000818:Animals; D056831:Coordination Complexes / Q000008:administration & dosage / Q000378:metabolism*; D004365:Drugs, Chinese Herbal / Q000008:administration & dosage / Q000378:metabolism*; D016166:Free Radical Scavengers / Q000008:administration & dosage / Q000378:metabolism*; D007275:Injections, Intravenous; D008297:Male; D008745:Methylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D027561:Salvia miltiorrhiza / Q000737:chemistry; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors*; D028561:Transition Elements / Q000737:chemistry / Q000378:metabolism*
chemical_list: D056831:Coordination Complexes; D004365:Drugs, Chinese Herbal; D016166:Free Radical Scavengers; D028561:Transition Elements; C061091:lithospermate B; D000254:Sodium-Potassium-Exchanging ATPase