Sun Jianghao, Yang Min, Han Jian, Wang Baorong, Ma Xiaochi, Xu Man, Liu Peng, Guo Dean
The State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100083, P. R. China.
Rapid Commun Mass Spectrom. 2007;21(14):2211-26. doi: 10.1002/rcm.3080.
Tanshinones are a class of bioactive constituents in the roots of Salvia miltiorrhiza named Dan-Shen in Chinese, which possess diverse pharmacological activities. In this study, we employed a sensitive high-performance liquid chromatography/multi-stage mass spectrometry (HPLC/MS(n)) method with data-dependent acquisition and a dynamic exclusion program for the identification of phase I metabolites of seven tanshinones in rat bile after intravenous administration. These seven tanshinones are tanshinone IIA, sodium tanshinone IIA sulfonate (abbreviated as STS, a water-soluble derivate of tanshinone IIA), cryptotanshinone, 15,16-dihydrotanshinone I, tanshinone IIB, przewaquinone A and tanshinone I. Altogether 33 metabolites underwent monohydroxylation, dihydroxylation, dehydrogenation, D-ring hydrolysis or oxidation reactions in the C-4 or C-15 side chain which were characterized by analyzing the LC/MS(n) data. Different metabolic reactions for tanshinones were dependent on the degree of saturation and the substituent group in the skeleton. Dehydrogenation was the major metabolic modification for cryptotanshinone with saturated A and D rings. 15,16-Dihydrotanshinone I containing a saturated D ring was mainly metabolized through D-ring hydrolysis. For tanshinone IIA, possessing a saturated A ring, hydroxylation was the major metabolic pathway. When there was hydroxyl group substitution in the C-17 or C-18 position, such as przewaquinone A and tanshinone IIB, or sulfonic group substitution in the C-16 position, such as STS, higher metabolic stability than that of tanshinone IIA was shown and only trace metabolites were generated. Oxidation in the C-4 or C-15 side chain was a characteristic reaction for tanshinone IIA and hydroxylated tanshinone IIA. For tanshinone I, bearing unsaturated A and D rings simultaneously, no metabolites were detected.
丹参酮是中药丹参根部的一类生物活性成分，具有多种药理活性。在本研究中，我们采用了一种灵敏的高效液相色谱/多级质谱（HPLC/MS(n)）方法，结合数据依赖采集和动态排除程序，用于鉴定大鼠静脉注射后胆汁中七种丹参酮的Ⅰ相代谢产物。这七种丹参酮分别是丹参酮ⅡA、丹参酮ⅡA磺酸钠（简称STS，丹参酮ⅡA的水溶性衍生物）、隐丹参酮、15,16-二氢丹参酮Ⅰ、丹参酮ⅡB、紫丹参醌A和丹参酮Ⅰ。通过分析LC/MS(n)数据，共鉴定出33种代谢产物，它们在C-4或C-15侧链上发生了单羟基化、二羟基化、脱氢、D环水解或氧化反应。丹参酮的不同代谢反应取决于骨架中的饱和度和取代基。对于具有饱和A环和D环的隐丹参酮，脱氢是主要的代谢修饰方式。含有饱和D环的15,16-二氢丹参酮Ⅰ主要通过D环水解进行代谢。对于具有饱和A环的丹参酮ⅡA，羟基化是主要的代谢途径。当C-17或C-18位有羟基取代时，如紫丹参醌A和丹参酮ⅡB，或C-16位有磺酸基取代时，如STS，它们表现出比丹参酮ⅡA更高的代谢稳定性，仅产生痕量代谢产物。C-4或C-15侧链的氧化是丹参酮ⅡA和羟基化丹参酮ⅡA的特征反应。对于同时具有不饱和A环和D环的丹参酮Ⅰ，未检测到代谢产物。
