Study on Toxicity Mechanism of Aconitum carmichaeli Lipid-soluble Alkaloids to Adjuvant-induced Arthritis Model Rats Based on Plasma Metabolomics / 中国药房

ABSTRACT

OBJECTIVE：To study the toxicity mechanism of lipid-soluble alkaloids of Aconitum carmichaeli to adjuvant-induced arthritis （AIA） model rats. METHODS： Totally 40 rats were randomly divided into blank group （ultrapure water）， model group （ultrapure water） and A. carmichaeli lipid-soluble alkaloids low-dose and high-dose groups （12.5， 35 mg/kg）， with 10 rats in each group. Except for blank group， rats in other groups were given complete Freund’s adjuvant 0.1 mL on the right hind paw to induce AIA model. 19 d after modeling， they were given relevant medicine intragastrically， once a day. After 14 d of administration， endogenous metabolites were separated and identified from plasma by UPLC-LTQ/Orbitrap MS. Then， the collected data were analyzed by principal component analysis （PCA） and partial least squares-discriminant analysis （PLS-DA）. Variable importance projection （VIP）＞1 and P value （＜0.05） were used to screen differential metabolites in plasma. Retrieving the database of Kyoto Encyclopedia of Genes and Genomes according to the differential metabolites，the toxic mechanism of A. carmichaeli liposoluble alkaloids to AIA rats were speculated. RESULTS： A total of 57 plasma metabolites were indentified， and 11 differential metabolites such as L-proline， 6-hydroxynicotinic acid and adenosine were identified. After inducing AIA model， the plasma contents of L-proline and uridylic acid were decreased significantly （P＜0.05 or P＜0.01）， and the content of deoxycytidine was increased significantly （P＜0.01）. Low dose of A. carmichaeli lipid-soluble alkaloids could decrease the plasma contents of adenosine and L-proline in rats （P＜0.05 or P＜0.01）， while the plasma contents of deoxycholic acid was increased significantly （P＜0.05）. High dose of A. carmichaeli lipid-soluble alkaloids could decrease the plasma contents of 6-hydroxynicotinic acid， adenosine， carnitine， L-proline， N-formylaminobenzoic acid were decreased significantly （P＜0.05 or P＜0.01）， while the plasma contents of deoxycholic acid， L-arginine， deoxycytidine and L-lysine were increased significantly （P＜0.05 or P＜0.01）. CONCLUSIONS： The toxicity of low-dose of A. carmichaeli lipid-soluble alkaloids to AIA model rats is less； the toxicity of high-dose of A. carmichaeli lipid-soluble alkaloids to AIA model rats may be related to abnormal bile secretion， lysine biosynthesis and metabolic disorders of purine， pyrimidine， tryptophan， proline and arginine.