Baker M E, Medlock K L, Sheehan D M
Department of Medicine, University of California, San Diego, La Jolla 92093-0623, USA.
Proc Soc Exp Biol Med. 1998 Mar;217(3):317-21. doi: 10.3181/00379727-217-44238.
There is considerable interest in the role(s) of plant-derived compounds such as bioflavonoids in regulating steroid hormone action in mammals, and in particular, the possible effects of the bioflavonoids on the growth of steroid-dependent breast and prostate tumors and on possible abnormal development of steroid-sensitive tissues. Studies of the hormone-like actions of bioflavonoids often use fetal or neonatal rats, which contain high levels of serum alpha-fetoprotein (AFP), a protein that binds estradiol with a Kd approximately 5 x 10(-9) M. Interaction of bioflavonoids with AFP could affect the availability of estrogens to estrogen-responsive cells, as well as the actions of bioflavonoids. These considerations motivated us to study the effect of several flavonoids (quercetin, rutin, naringenin, chrysin, apigenin, kaempferol, myricetin, morin, fisetin) and isoflavonoids (daidzein, genistein) on estrogen binding to rat AFP. We found that naringenin, a flavanone, and quercetin and kaempferol, flavonols, inhibit estrogen binding to AFP with apparent Kds of about 5 x 10(-7) M. To our surprise, the two isoflavonoids, daidzein and genistein, have Kds of about 5 x 10(-6) M for AFP. This 10-fold [correction of 1Q-fold] difference in affinity for AFP between flavonoids and isoflavonoids suggests that AFP has a specificity for the flavonoid structure. Moreover, the affinities of bioflavonoids for rat AFP are sufficiently high to suggest that flavonoids and isoflavonoids could modulate estradiol and estrone binding to rat AFP in vivo, when present at dietary levels. Additionally, the potency of the plant estrogens may be altered by binding to AFP. The flavonoids that we tested have different hydroxyl and glucoside substituents on the A, B, and C rings, which allows us to define some of the spatial requirements for binding to AFP. We find that 5,7-hydroxyl groups in ring A and a 4'-hydroxyl group in ring B are important for binding to AFP. This information, combined with molecular modeling studies, may elucidate the molecular basis for recognition of flavonoids and estrogens by AFP. Also, these findings indicate that the flavonoid levels in the diet need to be considered in studies of the effects of various xenobiotics and endocrine manipulations on experimental animals, particularly during development when serum estrogen binding protein concentrations are often elevated. Finally, bioflavonoids should be useful tools for understanding the variety of estrogen actions initiated by different structural classes of estrogens.
植物来源的化合物如生物类黄酮在调节哺乳动物类固醇激素作用方面备受关注，尤其是生物类黄酮对类固醇依赖性乳腺和前列腺肿瘤生长以及类固醇敏感组织可能的异常发育的潜在影响。对生物类黄酮激素样作用的研究通常使用胎鼠或新生大鼠，它们含有高水平的血清甲胎蛋白（AFP），这种蛋白以大约5×10⁻⁹ M的解离常数（Kd）结合雌二醇。生物类黄酮与AFP的相互作用可能会影响雌激素对雌激素反应性细胞的可利用性，以及生物类黄酮的作用。这些考虑促使我们研究几种黄酮类化合物（槲皮素、芦丁、柚皮素、白杨素、芹菜素、山奈酚、杨梅素、桑色素、非瑟酮）和异黄酮类化合物（大豆苷元、染料木黄酮）对雌激素与大鼠AFP结合的影响。我们发现，一种黄烷酮——柚皮素，以及黄酮醇——槲皮素和山奈酚，以约5×10⁻⁷ M的表观解离常数抑制雌激素与AFP的结合。令我们惊讶的是，两种异黄酮——大豆苷元和染料木黄酮，与AFP的解离常数约为5×10⁻⁶ M。黄酮类化合物和异黄酮类化合物对AFP亲和力的这种10倍差异表明AFP对黄酮类结构具有特异性。此外，生物类黄酮对大鼠AFP的亲和力足够高，表明当以饮食水平存在时，黄酮类化合物和异黄酮类化合物可能在体内调节雌二醇和雌酮与大鼠AFP的结合。此外，植物雌激素的效力可能会因与AFP结合而改变。我们测试的黄酮类化合物在A、B和C环上具有不同的羟基和葡萄糖苷取代基，可以让我们确定一些与AFP结合的空间要求。我们发现A环上的5,7 - 羟基和B环上的4' - 羟基对与AFP的结合很重要。这些信息与分子模拟研究相结合，可能会阐明AFP识别黄酮类化合物和雌激素的分子基础。此外，这些发现表明，在研究各种外源化合物和内分泌操作对实验动物的影响时，需要考虑饮食中的黄酮类化合物水平，特别是在发育过程中血清雌激素结合蛋白浓度经常升高的时候。最后，生物类黄酮应该会成为理解不同结构类别的雌激素引发的各种雌激素作用的有用工具。
