Metabolites and the pharmacokinetics of kobophenol A from Caragana sinica in rats
Introduction
Over the past 50 years, hormone replacement therapy (HRT) has been widely used to alleviate menopausal syndrome such as hot flashes, vaginal dryness, insomnia, etc. It can lower the occurrence of cardiovascular disease (CVD) to 40%, effectively prevent and cure osteoporosis especially. However, stoppage of HRT would lose therapy effects and long-term HRT introduce side effects (Karen and William, 1998). These side effects include weight put on, irregular vaginal discharge, the danger of breast cancer and endometrium cancer, etc. Recently, numerous research findings indicated that estrogen metabolites could stimulate or inhibit cancer growth (Lippert et al., 2000). These cause a big debate on HRT. Therefore, looking for effective phytoestrogen to replace HRT to prevent and cure the menopausal syndrome is now being the focus of research.
Caragana sinica (Buc’hoz) Rehd. (Fabaceae) is widely distributed in China. Its dried roots (Chinese name: Jinquegen) have been used in China as a folk medicine for the treatment of asthenia syndrome, vascular hypertension, leukorrhagia, bruises and contused wounds. In our previous study, we found that the major chemicals of the ethyl acetate extract of the roots were oligostilbenes, which have been found to have multi-faceted bioactivities (Luo et al., 2001). kobophenol A (1) (Fig. 1) is one of the leading chemicals. MTT assay showed that 1 is a phytoestrogen and can strongly stimulate the proliferation of osteoblasts cultured in vitro. Likely be developed as a new drug.
There were no research reports on the metabolites and the pharmacokinetics of 1. In the present investigation, metabolites of 1 in rats after orally treated were isolated and purified by multi-chromatography techniques. Three new metabolites of 1, were identified and named koboquinone A (M1), koboquinone B (M2) and koboquinone C (M3) (Fig. 2). The pharmacokinetic behavior of 1 in rats was characterized by HPLC assays. Following i.v. and oral administration of 1 to rats, the oral bioavailability and tissue distribution were evaluated.
Section snippets
Chemicals and reagents
Kobophenol A (1) was isolated from the roots of Caragana sinica accorded with the methods we had reported (Luo et al., 2001), 13.6 g (96.4%, measured by HPLC); structurally confirmed by comparing its 1H NMR and 13C NMR data with those reported (Kurihara et al., 1991). Methanol and acetonitrile used for HPLC analysis were of HPLC grade (Shanghai, China). Methanol for column chromatography was of analytical grade, dried and distilled immediately before use. Distilled water was purified with the
Metabolites M1–M3
M1 (13 mg) and M2 (3 mg) were isolated as reddish powder with a molecular formula of C56H42O14 by high-resolution electrospray ionization mass spectrometry (HRESI/MS). Structures were identified by 2D NMR spectra. They all gave pseudo-molecular ions [M–H]− at m/z 937. The MS/MS spectra of M1 and M2 were identical and showed fragment ions at m/z 815, 797, 709 and 691 (Fig. 3). The diagnostic ions at m/z 815 were 122 U lower than pseudo-molecular ions, which suggested the loss of the para-quinone
Discussion
M1 and M2 are novel phase I metabolic compounds of 1, structurally different to those natural occurring stilbene tetramers, which also have para-quinone structure (Ohyama et al., 1994, Ohyama et al., 1998). Our recent studies showed that they are metabolites of 1 under the action of intestinal bacteria (Liang et al., 2005).
For i.v. administration, there were no obvious difference in the pharmacokinetic parameter of t1/2 and CLtot among the doses. Additionally, AUC–dose relationship also showed
Acknowledgements
This study was supported by the National Science Foundation of China (30270155). The authors are grateful to professor Duan Li of our university for the instruction of our pharmacological experiments.
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