Jordan V C, Robinson S P
Fed Proc. 1987 Apr;46(5):1870-4.
The nonsteroidal antiestrogen tamoxifen exhibits a paradoxical species-specific pharmacology. The drug is a full estrogen in the mouse, a partial estrogen/antiestrogen in humans and the rat, and an antiestrogen in the chick oviduct. Inasmuch as tamoxifen has antiestrogenic effects in vitro, differential metabolism of tamoxifen to estrogens might occur in the species in which it has an estrogenic pharmacology. Tamoxifen or its metabolite 4-hydroxytamoxifen could lose the alkylaminoethane side chain to form the estrogenic compound metabolite E or bisphenol. Sensitive metabolic studies with [3H]tamoxifen in chicks, rats, and mice identified 4-hydroxytamoxifen as the major metabolite, but no potentially estrogenic metabolites were observed. Athymic mice with transplanted human breast tumors can be used to study the ability of tamoxifen to stimulate target tissue or tumor growth. Estradiol caused the growth of transplanted MCF-7 breast cancer cells into solid tumors and a uterotrophic response. However, tamoxifen does not support tumor growth when administered alone, although it stimulates uterine growth. Since a similar profile of metabolites is sequestered in human and mouse tissues, these studies strongly support the concept that the drug can selectively stimulate or inhibit events in the target tissues of different species without metabolic intervention.
非甾体类抗雌激素药物他莫昔芬表现出一种矛盾的物种特异性药理学特性。该药物在小鼠体内是一种完全的雌激素，在人类和大鼠体内是一种部分雌激素/抗雌激素，而在鸡输卵管中是一种抗雌激素。鉴于他莫昔芬在体外具有抗雌激素作用，在其具有雌激素药理学特性的物种中，他莫昔芬向雌激素的差异代谢可能会发生。他莫昔芬或其代谢产物4-羟基他莫昔芬可能会失去烷基氨基乙烷侧链，形成雌激素化合物代谢产物E或双酚。用[3H]他莫昔芬对鸡、大鼠和小鼠进行的敏感代谢研究确定4-羟基他莫昔芬为主要代谢产物，但未观察到潜在的雌激素代谢产物。移植了人乳腺肿瘤的无胸腺小鼠可用于研究他莫昔芬刺激靶组织或肿瘤生长的能力。雌二醇导致移植的MCF-7乳腺癌细胞生长为实体瘤并引起子宫营养反应。然而，单独给药时他莫昔芬不支持肿瘤生长，尽管它会刺激子宫生长。由于在人类和小鼠组织中隔离了相似的代谢产物谱，这些研究有力地支持了这样一种概念，即该药物可以在没有代谢干预的情况下选择性地刺激或抑制不同物种靶组织中的事件。
