hesperetin-3'-sulfate | 945038-48-2

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 黄酮类化合物
• 英文名称: hesperetin-3'-sulfate
• 英文别名: Hesperetin 3'-O-sulfate；Hesperetin 3'-sulfate；[5-[(2S)-5,7-dihydroxy-4-oxo-2,3-dihydrochromen-2-yl]-2-methoxyphenyl] hydrogen sulfate
• CAS: 945038-48-2
• 化学式: C₁₆H₁₄O₉S
• 分子量: 382.348
• InChiKey: AXWNOFHBYPBYNO-ZDUSSCGKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  26
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  148
• 氢给体数：
  3
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  橙皮素 在 6-氨基-9-[3-羟基-5-[(羟基-磺基氧基-磷酰)氧基甲基]-4-膦酰氧基-四氢呋喃-2-基]-嘌呤 、 magnesium chloride 作用下， 以 二甲基亚砜 为溶剂， 反应 0.08h， 生成 橙皮素7-O-硫酸盐 、 hesperetin-3'-sulfate
  参考文献：
  名称：

  Stereoselective Conjugation, Transport and Bioactivity ofS- andR-Hesperetin Enantiomers in Vitro

  摘要：

  The flavanone hesperetin ((+/-)-4'-methoxy-3',5,7-trihydroxyflavanone) is the aglycone of hesperidin, which is the major flavonoid present in sweet oranges. Hesperetin contains a chiral C-atom and so can exist as an S- and R-enantiomer, however, in nature 2S-hesperidin and its S-hesperetin aglycone are predominant. The present study reports a chiral HPLC method to separate S- and R-hesperetin on an analytical and semipreparative scale. This allowed characterization of the stereoselective differences in metabolism and transport in the intestine and activity in a selected bioassay of the separated hesperetin enantiomers in in vitro model systems: (1) with human small intestinal fractions containing UDP-glucuronosyl transferases (UGTs) or sulfotransferases (SULTs); (2) with Caco-2 cell monolayers as a model for the intestinal transport barrier; (3) with mouse Hepa-1c1c7 cells transfected with human EpRE-controlled luciferase to test induction of EpRE-mediated gene expression. The results obtained indicate some significant differences in the metabolism and transport characteristics and bioactivity between S- and R-hesperetin, however, these differences are relatively small. This indicates that for these end points, including intestinal metabolism and transport and EpRE-mediated gene induction, experiments performed with racemic hesperetin may adequately reflect what can be expected for the naturally occurring S-enantiomer. This is an important finding since at present hesperetin is only commercially available as a racemic mixture, while it exists in nature mainly as an S-enantiomer.

  DOI：

  10.1021/jf1008617

文献信息

• Phase II Metabolism of Hesperetin by Individual UDP-Glucuronosyltransferases and Sulfotransferases and Rat and Human Tissue Samples
  作者：Walter Brand、Marelle G. Boersma、Hanneke Bik、Elisabeth F. Hoek-van den Hil、Jacques Vervoort、Denis Barron、Walter Meinl、Hansruedi Glatt、Gary Williamson、Peter J. van Bladeren、Ivonne M. C. M. Rietjens

  DOI：10.1124/dmd.109.031047

  日期：2010.4

  Phase II metabolism by UDP-glucuronosyltransferases (UGTs) and sulfotransferases (SULTs) is the predominant metabolic pathway during the first-pass metabolism of hesperetin (4′-methoxy-3′,5,7-trihydroxyflavanone). In the present study, we have determined the kinetics for glucuronidation and sulfonation of hesperetin by 12 individual UGT and 12 individual SULT enzymes as well as by human or rat small intestinal, colonic, and hepatic microsomal and cytosolic fractions. Results demonstrate that hesperetin is conjugated at positions 7 and 3′ and that major enzyme-specific differences in kinetics and regioselectivity for the UGT and SULT catalyzed conjugations exist. UGT1A9, UGT1A1, UGT1A7, UGT1A8, and UGT1A3 are the major enzymes catalyzing hesperetin glucuronidation, the latter only producing 7- O -glucuronide, whereas UGT1A7 produced mainly 3′- O -glucuronide. Furthermore, UGT1A6 and UGT2B4 only produce hesperetin 7- O -glucuronide, whereas UGT1A1, UGT1A8, UGT1A9, UGT1A10, UGT2B7, and UGT2B15 conjugate both positions. SULT1A2 and SULT1A1 catalyze preferably and most efficiently the formation of hesperetin 3′- O -sulfate, and SULT1C4 catalyzes preferably and most efficiently the formation of hesperetin 7- O -sulfate. Based on expression levels SULT1A3 and SULT1B1 also will probably play a role in the sulfo-conjugation of hesperetin in vivo. The results help to explain discrepancies in metabolite patterns determined in tissues or systems with different expression of UGTs and SULTs, e.g., hepatic and intestinal fractions or Caco-2 cells. The incubations with rat and human tissue samples support an important role for intestinal cells during first-pass metabolism in the formation of hesperetin 3′- O -glucuronide and 7- O -glucuronide, which appear to be the major hesperetin metabolites found in vivo.

  在橙皮素（4′-甲氧基-3′,5,7-三羟基黄烷酮）的首过代谢过程中，UDP-葡萄糖醛酸转移酶（UGTs）和磺酸转移酶（SULTs）的二期代谢是最主要的代谢途径。在本研究中，我们测定了 12 种 UGT 酶和 12 种 SULT 酶以及人或大鼠小肠、结肠和肝微粒体和细胞膜部分对橙皮素进行葡萄糖醛酸化和磺化的动力学。研究结果表明，橙皮素在第 7 位和第 3′位发生共轭，UGT 和 SULT 催化共轭的动力学和区域选择性存在重大的酶特异性差异。UGT1A9、UGT1A1、UGT1A7、UGT1A8 和 UGT1A3 是催化橙皮素葡萄糖醛酸化的主要酶，后者只产生 7- O -葡萄糖醛酸，而 UGT1A7 则主要产生 3′- O -葡萄糖醛酸。此外，UGT1A6 和 UGT2B4 只产生橙皮素 7- O -葡萄糖醛酸，而 UGT1A1、UGT1A8、UGT1A9、UGT1A10、UGT2B7 和 UGT2B15 则在这两个位置进行共轭。SULT1A2 和 SULT1A1 催化并最有效地形成橙皮素 3′- O -硫酸盐，而 SULT1C4 催化并最有效地形成橙皮素 7- O -硫酸盐。根据表达水平，SULT1A3 和 SULT1B1 也可能在体内橙皮素的硫代结合中发挥作用。这些结果有助于解释在 UGTs 和 SULTs 表达不同的组织或系统（如肝脏和肠道部分或 Caco-2 细胞）中测定的代谢物模式的差异。大鼠和人体组织样本的培养结果表明，肠道细胞在形成橙皮素 3′- O -葡萄糖醛酸苷和 7- O -葡萄糖醛酸苷的首过代谢过程中发挥了重要作用，而这两种物质似乎是在体内发现的主要橙皮素代谢物。
• Stereoselective Conjugation, Transport and Bioactivity of<i>S</i>- and<i>R</i>-Hesperetin Enantiomers in Vitro
  作者：Walter Brand、Jia Shao、Elisabeth F. Hoek-van den Hil、Kathelijn N. van Elk、Bert Spenkelink、Laura H. J. de Haan、Maarit J. Rein、Fabiola Dionisi、Gary Williamson、Peter J. van Bladeren、Ivonne M. C. M. Rietjens

  DOI：10.1021/jf1008617

  日期：2010.5.26

  The flavanone hesperetin ((+/-)-4'-methoxy-3',5,7-trihydroxyflavanone) is the aglycone of hesperidin, which is the major flavonoid present in sweet oranges. Hesperetin contains a chiral C-atom and so can exist as an S- and R-enantiomer, however, in nature 2S-hesperidin and its S-hesperetin aglycone are predominant. The present study reports a chiral HPLC method to separate S- and R-hesperetin on an analytical and semipreparative scale. This allowed characterization of the stereoselective differences in metabolism and transport in the intestine and activity in a selected bioassay of the separated hesperetin enantiomers in in vitro model systems: (1) with human small intestinal fractions containing UDP-glucuronosyl transferases (UGTs) or sulfotransferases (SULTs); (2) with Caco-2 cell monolayers as a model for the intestinal transport barrier; (3) with mouse Hepa-1c1c7 cells transfected with human EpRE-controlled luciferase to test induction of EpRE-mediated gene expression. The results obtained indicate some significant differences in the metabolism and transport characteristics and bioactivity between S- and R-hesperetin, however, these differences are relatively small. This indicates that for these end points, including intestinal metabolism and transport and EpRE-mediated gene induction, experiments performed with racemic hesperetin may adequately reflect what can be expected for the naturally occurring S-enantiomer. This is an important finding since at present hesperetin is only commercially available as a racemic mixture, while it exists in nature mainly as an S-enantiomer.