Tamoxifen N-Glucuronide

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 二苯乙烯类
• 英文名称: Tamoxifen N-Glucuronide
• 英文别名: tamoxifen N-beta-D-glucosiduronic acid；[(2R,3R,4S,5S,6S)-6-carboxy-3,4,5-trihydroxyoxan-2-yl]-[2-[4-[(Z)-1,2-diphenylbut-1-enyl]phenoxy]ethyl]-dimethylazanium
• 化学式: C₃₂H₃₈NO₇
• 分子量: 548.656
• InChiKey: UKFQQYJAYUAYES-DTMHFWPESA-O

计算性质

• 辛醇/水分配系数(LogP)：
  5.3
• 重原子数：
  40
• 可旋转键数：
  10
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.34
• 拓扑面积：
  116
• 氢给体数：
  4
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  他莫昔芬 在 碳酸氢钠 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 反应 36.0h， 生成 Tamoxifen N-Glucuronide
  参考文献：
  名称：

  Quaternary ammonium-linked glucuronidation of tamoxifen by human liver microsomes and UDP-glucuronosyltransferase 1A4

  摘要：

  Tamoxifen (TAM), a nonsteroidal antiestrogen, is the most widely used drug for chemotherapy of hormone-dependent breast cancer in women. In the present study, we found a new potential metabolic pathway of TAM via N-linked glucuronic acid conjugation for excretion in humans. TAM N+ -glucuronide was isolated from a reaction mixture consisting of TAM and human liver microsomes fortified with UDP-glucuronic acid (UDPGA) and identified with a synthetic specimen by high-performance liquid chromatography-electrospray ionization-mass spectrometry. However, no TAM-glucuronidating activity was detected in microsomes from rat, mouse, monkey, dog, and guinea pig livers. A strong correlation (r(2) = 0.92) was observed between N-glucuronidating activities toward TAM and trifluoperazine, a probe substrate for human UDP-glucuronosyltransferase (UGT) 1A4, in human liver microsomes from eight donors (five females, three males). However, no correlation (r(2) = 0.02) was observed in the activities between 7-hydroxy-4-(trifluoromethyl)coumarin and TAM. Only UGT1A4 catalyzed the N-linked glucuronidation of TAM among recombinant UGTs (UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B4, UGT2B7, UGT2B15, and UGT2B17) expressed in insect cells. Apparent K-m values for TAM N-glucuronidation by human liver microsomes and recombinant UGT1A4 were 35.8 and 3 2.4 muM, respectively. These results strongly suggested that UGT1A4 could play a role in metabolism and excretion of TAM without Phase I metabolism in human liver. TAM N+-glucuronide still had binding affinity similar to TAM itself for human estrogen receptors, ERalpha and ERbeta, suggesting that TAM N+-glucuronide might contribute to the biological activity of TAM in vivo. (C) 2004 Elsevier Inc. All rights reserved.

  DOI：

  10.1016/j.bcp.2004.02.014