Metabolism of [6]-Shogaol in Mice and in Cancer Cells
Metabolism of [6]-Shogaol in Mice and in Cancer Cells
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DOI：
10.1124/dmd.111.043331
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发表时间：
2012-04-01
影响因子：
3.9
通讯作者：
Sang, Shengmin
中科院分区：
文献类型：
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作者：
Chen, Huadong;Lv, Lishuang;Sang, Shengmin
生姜因具有抗氧化、抗炎、抗肿瘤等活性而受到广泛关注。然而，其主要成分的代谢命运仍不明朗。在本研究中，首次研究了生姜中的主要活性成分[6]-shogaol在小鼠和癌细胞中的代谢。检测和鉴定了13种代谢物，其中7种是从用shogaol处理的小鼠的粪便样本中纯化出来的。其结构分别鉴定为1-(4‘-羟基-3’-甲氧基苯基)-4-癸烯-3-醇(M6)，5-methoxy-1-(4‘-hydroxy-3’-methoxyphenyl)-decan-3-one(M7)，3‘，4’-二羟基苯基-3-酮(M8)，1-(4‘-羟基-3’-甲氧基苯基)-3-醇(M9)，5-methylthio-1-(4‘-hydroxy-3’-methoxyphenyl)-decan-3-one(M10)，1-(4‘-羟基-3’-甲氧基苯基)-1-(4‘-羟基-3’-甲氧基苯基)-迪康-3-酮(M11)和5-methylthio-1-(4‘-hydroxy-3’-methoxyphenyl)-decan-3-ol(M12)。其余代谢物经MSN(n=1~3)谱图分析和标准对照鉴定为5-半胱氨基-M6(M1)、5-半胱氨基-[6]-shogaol(M2)、5-半胱氨基-甘氨酰-M6(M3)、5-N-乙酰半胱氨基-M6(M4)、5-N-乙酰半胱氨基-[6]-shogaol(M5)和5-谷胱甘醇-[6]-shogaol(M13)。在代谢物中，M1至M5、M10、M12和M13被鉴定为[6]-shogaol及其代谢物M6的硫醇结合物。M9和M11是四种不同癌细胞系(HCT-116、HT-29、H-1299和CL-13)的主要代谢物，而M13是HCT-116人结肠癌细胞的主要代谢物。我们进一步证明M9和M11是具有生物活性的化合物，能够抑制癌细胞的生长并诱导人癌细胞的凋亡。我们的结果表明：1)[6]-shogaol在这两个模型中被广泛代谢，2)其代谢产物是生物活性化合物，3)硫代尿酸途径是[6]-shogaol的主要生物转化途径之一。
Ginger has received extensive attention because of its antioxidant, anti-inflammatory, and antitumor activities. However, the metabolic fate of its major components is still unclear. In the present study, the metabolism of [6]-shogaol, one of the major active components in ginger, was examined for the first time in mice and in cancer cells. Thirteen metabolites were detected and identified, seven of which were purified from fecal samples collected from [6]-shogaol-treated mice. Their structures were elucidated as 1-(4'-hydroxy-3'-methoxyphenyl)-4-decen-3-ol (M6), 5-methoxy-1-(4'-hydroxy-3'-methoxyphenyl)-decan-3-one (M7), 3',4'-dihydroxyphenyl-decan-3-one (M8), 1-(4'-hydroxy-3'-methoxyphenyl)-decan-3-ol (M9), 5-methylthio-1-(4'-hydroxy-3'-methoxyphenyl)-decan-3-one (M10), 1-(4'-hydroxy-3'-methoxyphenyl)-decan-3-one (M11), and 5-methylthio-1-(4'-hydroxy-3'-methoxyphenyl)-decan-3-ol (M12) on the basis of detailed analysis of their H-1, C-13, and two-dimensional NMR data. The rest of the metabolites were identified as 5-cysteinyl-M6 (M1), 5-cysteinyl-[6]-shogaol (M2), 5-cysteinylglycinyl-M6 (M3), 5-N-acetylcysteinyl-M6 (M4), 5-N-acetylcysteinyl-[6]-shogaol (M5), and 5-glutathiol-[6]-shogaol (M13) by analysis of the MSn (n = 1-3) spectra and comparison to authentic standards. Among the metabolites, M1 through M5, M10, M12, and M13 were identified as the thiol conjugates of [6]-shogaol and its metabolite M6. M9 and M11 were identified as the major metabolites in four different cancer cell lines (HCT-116, HT-29, H-1299, and CL-13), and M13 was detected as a major metabolite in HCT-116 human colon cancer cells. We further showed that M9 and M11 are bioactive compounds that can inhibit cancer cell growth and induce apoptosis in human cancer cells. Our results suggest that 1) [6]-shogaol is extensively metabolized in these two models, 2) its metabolites are bioactive compounds, and 3) the mercapturic acid pathway is one of the major biotransformation pathways of [6]-shogaol.