Ruenitz P C, Thompson C B, Srivatsan V
College of Pharmacy, University of Georgia, Athens 30602.
J Steroid Biochem. 1989 Sep;33(3):365-9. doi: 10.1016/0022-4731(89)90325-7.
Besides undergoing O-demethylation in vivo, the triarylethylene antiestrogen nitromifene [1-(4-(2-pyrrolidinylethoxy)phenyl)-1-(4-methoxy)-phenyl-2-phenyl- 2- nitroethene, 1] undergoes biotransformation via nitroreduction, ethene bond cleavage, and pyrrolidine ring oxidation affording ketone metabolites 2 and 3 and a lactam metabolite 4. Estrogen receptor (ER) affinities of 1, 2, and 4 were, in turn, 1.7, 0.1, and 3.8% that of estradiol in MCF 7 human breast cancer cells, and these compounds inhibited by 50% the proliferation of MCF 7 cells at respective concentrations of 1.1, 5.6, and 2.0 microM. The inhibitory effect of 4 was fully reversible by estradiol, but that of 2 was only partially reversible. Also 3, which did not interact with ER, inhibited proliferation by 44% at a concentration of 10 microM. These results suggested that in contrast to 4, the effects of 2 and 3 were due in part to interaction with sites distinct from ER. Antiestrogen binding sites and calmodulin have been suggested to mediate antiproliferative effects of drugs. Interaction of ligands with the former sites has been proposed to antagonize the growth promoting effect of histamine. Although 2 and 3 had high affinities for these sites, their inhibitory effects on MCF 7 cell growth were largely unaffected by the presence of histidine, the source of intracellular histamine. Thus, the relationship between antiestrogen binding site affinity and antiproliferative effects of 2 and 3 was not clarified. In contrast, MCF 7 cell growth suppression potencies paralleled calmodulin antagonist potencies of 1 and 2 suggesting that interaction of 1 and 2 with calmodulin may contribute to their anticancer effects.
三芳基乙烯抗雌激素硝米芬[1-(4-(2-吡咯烷基乙氧基)phenyl)-1-(4-甲氧基)phenyl-2-phenyl-2-硝基乙烯，1]除了在体内进行O-去甲基化外，还通过硝基还原、乙烯键断裂和吡咯烷环氧化进行生物转化，生成酮代谢物2和3以及内酰胺代谢物4。在MCF 7人乳腺癌细胞中，1、2和4与雌激素受体(ER)的亲和力分别为雌二醇的1.7%、0.1%和3.8%，并且这些化合物在各自浓度为1.1、5.6和2.0 microM时可抑制MCF 7细胞增殖50%。4的抑制作用可被雌二醇完全逆转，但2的抑制作用仅部分可逆。同样，不与ER相互作用的3在浓度为10 microM时可抑制增殖44%。这些结果表明，与4相反，2和3的作用部分是由于与不同于ER的位点相互作用。抗雌激素结合位点和钙调蛋白已被认为介导药物的抗增殖作用。有人提出配体与前者位点的相互作用可拮抗组胺的生长促进作用。尽管2和3对这些位点具有高亲和力，但它们对MCF 7细胞生长的抑制作用在很大程度上不受细胞内组胺来源组氨酸存在的影响。因此，2和3的抗雌激素结合位点亲和力与抗增殖作用之间的关系尚未阐明。相比之下，MCF 7细胞生长抑制效力与1和2的钙调蛋白拮抗剂效力平行，表明1和2与钙调蛋白的相互作用可能有助于它们的抗癌作用。
