Estrogen regulation of methyl p-hydroxyphenyllactate hydrolysis: correlation with estrogen stimulation of rat uterine growth.
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.
Markaverich
B M
BM
Center for Biotechnology, Baylor College of Medicine, The Woodlands, TX 77381.
Gregory
R R
RR
Alejandro
M A
MA
Varma
R S
RS
Johnson
G A
GA
Middleditch
B S
BS
D000818:Animals; D002451:Cell Compartmentation; D002845:Chromatography; D003600:Cytosol / Q000378:metabolism; D004950:Esterases / Q000378:metabolism; D004967:Estrogens / Q000502:physiology*; D005260:Female; D006358:Hot Temperature; D007700:Kinetics; D007773:Lactates / Q000378:metabolism*; D010666:Phenylpropionates / Q000378:metabolism; D051381:Rats; D013379:Substrate Specificity; D014599:Uterus / Q000201:enzymology*
D004967:Estrogens; D007773:Lactates; D010666:Phenylpropionates; C001418:4-hydroxyphenyllactic acid; C055915:methyl 4-hydroxyphenyllactate; D004950:Esterases