Markaverich B M, Gregory R R, Alejandro M A, Varma R S, Johnson G A, Middleditch B S
Center for Biotechnology, Baylor College of Medicine, The Woodlands, TX 77381.
J Steroid Biochem. 1989 Nov;33(5):867-76. doi: 10.1016/0022-4731(89)90234-3.
We have recently demonstrated that methyl p-hydroxyphenyllactate (MeHPLA) is the endogenous ligand for nuclear type II binding sites in the rat uterus and other estrogen target and non-target tissues. MeHPLA binds to nuclear type II binding sites with a very high binding affinity (Kd approximately 4-5 nM), blocks uterine growth in vivo, and inhibits MCF-7 human breast cancer cell growth in vitro. Conversely, the free acid (p-hydroxyphenyllactic acid, HPLA) interacts with type II binding sites with a much lower affinity (Kd approximately 200 nM) and does not inhibit estrogen-induced uterine growth in vivo or MCF-7 cell growth in vitro. On the basis of these observations, we suggested that one way that estrogen may override MeHPLA inhibition of rat uterine growth may be to stimulate esterase hydrolysis of MeHPLA to HPLA. The present studies demonstrate that the rat uterus does contain an esterase (mol. wt approximately 50,000) which cleaves MeHPLA to HPLA, and that this enzyme is under estrogen regulation. This conclusion is supported by the observations that MeHPLA esterase activity is increased 2-3-fold above controls within 2-4 h following a single injection of estradiol, and is maintained at high levels for 16-24 h following hormone administration. This sustained elevation of MeHPLA esterase activity correlates with estradiol stimulation of true uterine growth and DNA synthesis.
我们最近证实，对羟基苯乳酸甲酯（MeHPLA）是大鼠子宫及其他雌激素靶组织和非靶组织中核II型结合位点的内源性配体。MeHPLA以非常高的结合亲和力（解离常数Kd约为4 - 5 nM）与核II型结合位点结合，在体内可抑制子宫生长，在体外可抑制MCF - 7人乳腺癌细胞生长。相反，游离酸（对羟基苯乳酸，HPLA）与II型结合位点的相互作用亲和力低得多（Kd约为200 nM），且在体内不抑制雌激素诱导的子宫生长，在体外也不抑制MCF - 7细胞生长。基于这些观察结果，我们推测雌激素可能克服MeHPLA对大鼠子宫生长抑制作用的一种方式可能是刺激MeHPLA酯酶水解生成HPLA。目前的研究表明，大鼠子宫确实含有一种酯酶（分子量约为50,000），可将MeHPLA裂解为HPLA，且该酶受雌激素调控。单次注射雌二醇后2 - 4小时内，MeHPLA酯酶活性比对照组增加2 - 3倍，并在激素给药后16 - 24小时维持在高水平，这一观察结果支持了上述结论。MeHPLA酯酶活性的持续升高与雌二醇对子宫真正生长和DNA合成的刺激作用相关。
