In vitro inhibitory effects of ethanol extract of Danshen (Salvia miltiorrhiza) and its components on the catalytic activity of soluble epoxide hydrolase.
BACKGROUND
Soluble epoxide hydrolase (sEH) has been demonstrated to be a key enzyme involved in the pathologic development of several cardiovascular diseases and inflammation, and inhibition of sEH is therefore very helpful or crucial for the treatment of ischemia-reperfusion injury, cardiac hypertrophy, hypertension and inflammation. Danshen, the dried root of Salvia miltiorrhiza (Fam. Labiatae), has been used for the treatment of cardiovascular and cerebrovascular diseases in China and other countries for hundreds of years. Recent studies indicated that Danshen and its preparations also have potential for the management of inflammation. However, little information is available about the possibility of Danshen and its components on sEH inhibition.


OBJECTIVE
Danshen extracts and its constituents were tested for sEH inhibition using its physiological substrate, 8,9-EET, based on a LC-MS/MS assay in this study.


RESULTS
Among the tested 15 compounds, tanshinone IIA and cryptotanshinone were found to be the potent (Ki = 0.87 μM) and medium (Ki = 6.7 μM) mixed-type inhibitors of sEH, respectively. Salvianolic acid C (Ki = 8.6 μM) was proved to be a moderate noncompetitive sEH inhibitor. In consistent with the inhibition results of the pure compounds, the 75% ethanol extract of Danshen (EE, IC50 = 86.5 μg/ml) which contained more tanshinone IIA and cryptotanshinone exhibited more potent inhibition on sEH than the water extract (WE, IC50 > 200 μg/ml) or 1 M NaHCO3 (BE, IC50 > 200 μg/ml) extract.


CONCLUSIONS
These data indicated that using the ethanol fraction of Danshen and increasing the amounts of tanshinone IIA, cryptotanshinone and salvianolic acid C, especially the contents of tanshinone IIA in Danshen extract or preparations to enhance the inhibitory effects on sEH might be efficient ways to improve its cardiovascular protective and anti-inflammatory effects, and that herbal medicines could be an untapped reservoir for sEH-inhibition agents and developing sEH inhibitors from the cardiovascular protective and anti-inflammatory herbs is a promising approach.
State Key Laboratory of Natural Medicines, China Pharmaceutical University, No. 24 Tongjia Lane, Nanjing 210009, China; Department of Clinical Pharmacology, Affiliated Hospital of Nanjing University of Traditional Chinese Medicine, No. 155 Hanzhong Road, Nanjing 210029, China.
Meijuan
M
Xu
State Key Laboratory of Natural Medicines, China Pharmaceutical University, No. 24 Tongjia Lane, Nanjing 210009, China.
Haiping
H
Hao
State Key Laboratory of Natural Medicines, China Pharmaceutical University, No. 24 Tongjia Lane, Nanjing 210009, China.
Lifeng
L
Jiang
State Key Laboratory of Natural Medicines, China Pharmaceutical University, No. 24 Tongjia Lane, Nanjing 210009, China.
Fang
F
Long
State Key Laboratory of Natural Medicines, China Pharmaceutical University, No. 24 Tongjia Lane, Nanjing 210009, China.
Yidan
Y
Wei
State Key Laboratory of Natural Medicines, China Pharmaceutical University, No. 24 Tongjia Lane, Nanjing 210009, China.
Hui
H
Ji
Department of Clinical Pharmacology, Affiliated Hospital of Nanjing University of Traditional Chinese Medicine, No. 155 Hanzhong Road, Nanjing 210029, China.
Bingting
B
Sun
State Key Laboratory of Natural Medicines, China Pharmaceutical University, No. 24 Tongjia Lane, Nanjing 210009, China.
Ying
Y
Peng
State Key Laboratory of Natural Medicines, China Pharmaceutical University, No. 24 Tongjia Lane, Nanjing 210009, China.
Guangji
G
Wang
Department of Clinical Pharmacology, Affiliated Hospital of Nanjing University of Traditional Chinese Medicine, No. 155 Hanzhong Road, Nanjing 210029, China. Electronic address: ju_njxmj@126.com.
Wenzheng
W
Ju
State Key Laboratory of Natural Medicines, China Pharmaceutical University, No. 24 Tongjia Lane, Nanjing 210009, China. Electronic address: liping2004@126.com.
Ping
P
Li
D045784:Abietanes / Q000494:pharmacology; D000475:Alkenes / Q000494:pharmacology; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D000431:Ethanol; D006801:Humans; D010616:Phenanthrenes / Q000494:pharmacology; D010936:Plant Extracts / Q000494:pharmacology*; D059808:Polyphenols / Q000494:pharmacology; D027561:Salvia miltiorrhiza / Q000737:chemistry*; D001572:Benzofurans
D045784:Abietanes; D000475:Alkenes; D004365:Drugs, Chinese Herbal; D004851:Epoxide Hydrolases; D000431:Ethanol; D010616:Phenanthrenes; D010936:Plant Extracts; D059808:Polyphenols; C021751:tanshinone; C028972:dan-shen root extract; C037886:cryptotanshinone; C000597819:salvianolic acid C; D001572:Benzofurans
Cryptotanshinone; Danshen (Salvia miltiorrhiza); Inhibitor; Salvianolic acid C; Soluble epoxide hydrolase (sEH); Tanshinone IIA