ESTROGEN REGULATION OF METHYL PARA-HYDROXYPHENYLACTATE HYDROLYSIS - CORRELATION WITH ESTROGEN STIMULATION OF RAT UTERINE GROWTH
ESTROGEN REGULATION OF METHYL PARA-HYDROXYPHENYLACTATE HYDROLYSIS - CORRELATION WITH ESTROGEN STIMULATION OF RAT UTERINE GROWTH
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DOI：
10.1016/0022-4731(89)90234-3
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发表时间：
1989-11-01
影响因子：
4.1
通讯作者：
MIDDLEDITCH, BS
中科院分区：
文献类型：
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作者：
MARKAVERICH, BM;GREGORY, RR;MIDDLEDITCH, BS
我们最近已经证明，甲基对羟基苯乳酸（MeHPLA）是内源性配体的核II型结合位点在大鼠子宫和其他雌激素靶和非靶组织。MeHPLA以非常高的结合亲和力（Kd apprx. 4-5 nM），在体内阻断子宫生长，并在体外抑制MCF-7人乳腺癌细胞生长。相反，游离酸（对羟基苯基乳酸，HPLA）与II型结合位点以低得多的亲和力（Kd apprx. 200 nM），并且不抑制体内雌激素诱导的子宫生长或体外MCF-7细胞生长。基于这些观察结果，我们认为雌激素可以克服MeHPLA对大鼠子宫生长的抑制的一种方式可能是刺激MeHPLA向HPLA的酯酶水解。本研究证实大鼠子宫内含有一种酯酶（mol.约重量50，000），其将MeHPLA切割成HPLA，并且该酶受雌激素调节。这一结论得到以下观察结果的支持：在单次注射雌二醇后2-4小时内，MeHPLA酯酶活性比对照增加2-3倍，并且在激素给药后16- 2 - 4小时内保持在高水平。这种持续升高的MeHPLA酯酶活性与雌二醇刺激真实子宫生长和DNA合成相关。
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 .apprx. 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 .apprx. 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 uterine does contain an esterase (mol. wt .apprx. 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.