他莫昔芬在离体大鼠肝细胞中的代谢。4-羟基他莫昔芬葡萄糖醛酸苷的鉴定。

Metabolism of tamoxifen by isolated rat hepatocytes. Identification of the glucuronide of 4-hydroxytamoxifen.

作者信息

McCague R, Parr I B, Leclercq G, Leung O T, Jarman M

机构信息

Drug Development Section, Cancer Research Campaign Laboratory, Institute of Cancer Research, Sutton, Surrey, U.K.

出版信息

Biochem Pharmacol. 1990 May 1;39(9):1459-65. doi: 10.1016/0006-2952(90)90427-m.

DOI:10.1016/0006-2952(90)90427-m

PMID:2334445

Abstract

Metabolism of 4-hydroxytamoxifen by hepatocytes isolated from rats administered with phenobarbital and examination by TLC of the components not extractable into ethyl acetate revealed 4-hydroxytamoxifen beta-glucuronide; its identity was confirmed by comparison of its 1H NMR spectrum with that of synthetic material. This conjugate was also formed on metabolism of tamoxifen. It bound to cytosolic oestrogen receptors with only one thousandth the affinity of 4-hydroxytamoxifen and gave a correspondingly very weak inhibition of growth of the MCF-7 human breast cancer cell line. Therefore, in contrast to reported observations on the 3-glucuronide of oestradiol, the MCF-7 cells were unable to hydrolyse 4-hydroxytamoxifen glucuronide and on this evidence, formation of this metabolite is solely a deactivation pathway.

摘要

用苯巴比妥处理过的大鼠分离出的肝细胞对4-羟基他莫昔芬进行代谢，并通过薄层色谱法对不能萃取到乙酸乙酯中的成分进行检测，结果显示存在4-羟基他莫昔芬β-葡萄糖醛酸苷；通过将其1H NMR光谱与合成材料的光谱进行比较，证实了其结构。这种缀合物在他莫昔芬的代谢过程中也会形成。它与胞质雌激素受体结合，亲和力仅为4-羟基他莫昔芬的千分之一，因此对MCF-7人乳腺癌细胞系的生长抑制作用相应非常微弱。因此，与关于雌二醇3-葡萄糖醛酸苷的报道观察结果相反，MCF-7细胞无法水解4-羟基他莫昔芬葡萄糖醛酸苷，基于此证据，这种代谢物的形成仅仅是一种失活途径。