Lack of Cell Proliferative and Tumorigenic Effects of 4-Hydroxyestradiol in the Anterior Pituitary of Rats: Role of Ultrarapid O-Methylation Catalyzed by Pituitary Membrane-Bound Catechol-O-Methyltransferase

Abstract

In animal models, estrogens are complete carcinogens in certain target sites. 4-Hydroxyestradiol (4-OH-E), an endogenous metabolite of 17β-estradiol (E), is known to have prominent estrogenic activity plus potential genotoxicity and mutagenicity. We report here our finding that 4-OH-E does not induce pituitary tumors in ACI female rats, whereas E produces 100% pituitary tumor incidence. To probe the mechanism, we conducted a short-term animal experiment to compare the proliferative effect of 4-OH-E in several organs. We found that, whereas 4-OH-E had little ability to stimulate pituitary cell proliferation in ovariectomized female rats, it strongly stimulates cell proliferation in certain brain regions of these animals. Further, when we used in vitro cultured rat pituitary tumor cells as models, we found that 4-OH-E has similar efficacy as E in stimulating cell proliferation, but its potency is approximately 3 orders of magnitude lower than that of E. Moreover, we found that the pituitary tumor cells have the ability to selectively metabolize 4-OH-E (but not E) with ultrahigh efficiency. Additional analysis revealed that the rat pituitary expresses a membrane-bound catechol-O-methyltransferase that has an ultralow K value (in nM range) for catechol estrogens. On the basis of these observations, it is concluded that rapid metabolic disposition of 4-OH-E through enzymatic O-methylation in rat anterior pituitary cells largely contributes to its apparent lack of cell proliferative and tumorigenic effects in this target site.

Exploration of the Effects of TGF-β Pathway-Based Pituitary Tumor of Rats on GH3 Cell Line after Intervention with Different Concentrations of TGZ

“…In gastric cancer and cervical cancer, MMP-9 has also been found to play an important role in cell metastasis and infiltration. The occurrence, development, invasion, and migration of central nervous system tumors also closely concern MMP-9 [ 19 ]. The relationship between glioma and MMP-9 has been deeply studied, and an extensive number of experimental data show that MMP-9 promotes the proliferation of glioma-infiltrating tissue cells.…”