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 (Mg2+, Zn2+, Cr3+, Co2+, Ni2+ and Mn2+) 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 Mg2+, Zn2+, Cr3+, Ni2+ or Mn2+, LSB and its four putative metabolites were equivalently detected in their bile samples. Mn2+-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 Mg2+-LSB, Zn2+-LSB and Mn2+-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 Co2+-LSB died.
Conclusion:
Zn2+-LSB, Cr3+-LSB, Ni2+-LSB or Mn2+-LSB produces identical four methylated metabolites of LSB in rats, and seemed to be as safe as LSB or Mg2+-LSB.
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Acknowledgements
The work was supported by a grant to Jason TC TZEN of National Chung-Hsing University (NCHU-102D604), Taiwan, China.
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Chen, YJ., Chung, Ty., Chen, WY. et al. Detecting metabolites of different transition metallithospermate B complexes after intravenous injection in rats. Acta Pharmacol Sin 35, 937–944 (2014). https://doi.org/10.1038/aps.2014.37
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DOI: https://doi.org/10.1038/aps.2014.37
