Estrogen synthetase

There is some iiterature that examines fiavonoids such as apigenin as iigands for the estrogen beta receptor, and as an inhibitor of the enzyme estrogen synthetase (aromatase) (Kuiper et ai. 1998 Keiiis and Vickery 1984). These compounds do so potentiy, but the behaviorai significance of amounts observed in common preparations needs to be further investigated. 

Kellis JT Jr, Vickery LE. (1984). Inhibition of human estrogen synthetase (aromatase) by flavones. Science. 225(4666) 1032-34. 

Kao, Y.C. et al., Molecular basis of the inhibition of human aromatase (estrogen synthetase) by flavone and isoflavone phytoestrogens a site-directed mutagenesis study, Environ. Health Per-spect., 106, 85, 1998. 

The conversion of androstenedione to estrone is catalyzed by aromatase. Inhibition of aromatase (human estrogen synthetase) by several naturally occurring flavonoids, including quercetin, chrysin, and apigenin, has been described. The synthetic flavone 7,8-benzoflavone was most active. Aromatization of androstenedione was affected by several flavonoids, of which 7-hydroxy-flavone and 7,4-dihydroxyflavone were the most potent. 

Pregnancy in the monkey was terminated at a time when the ovaries are required for the continuation of pregnancy as well as when the placenta is capable of maintaining pregnancy in the absence of the ovaries. The estrogen synthetase blocker inhibited mating, ovulation, and implantation in rats.38 of a series of aromatase inhibitors, 23 was the most active in vitro.39... 

Scheme 4.35 Mechanism of action of the irreversible estrogen synthetase inhibitor 19,19-di-fluoroandrostendione right [3, 80] compared with the normal course of the aromatase reaction left) (Nu = nucleophilic group).

In order to study estrogen synthetase inhibitors, it was necessary to prepare the carbinol (267). This compound was obtained from the corresponding A -methylpyrimidinium salt (266 Ar=p-chlorophenyl) <90JMC416>. 

Enterolactone had been described as a moderate competitive inhibitor of human estrogen synthetase (aromatase) and it binds to or near the substrate region of the active site of the P-450 enzyme [61], In another study [89], seven lignans were evaluated for their abilities to inhibit aromatase enzyme activity in a human preadipose cell culture system. The lignan enterolactone and its precursors, didemethoxymatairesinol and 3 -demethoxy-3-<9-demethylmatairesinol, decreased aromatase enzyme activity, with Ki values... 

Marcotte, P.A. and C.H. Robinson (1982). Inhibition and inactivation of estrogen synthetase (aromatase) by fluorinated substrate analogues. Biochemistry 21, 2773-2778. 

Simoncini T, Genazzani AR, Liao JK (2002a) Nongenomic mechanisms of endothelial nitric oxide synthetase activation by the selective estrogen receptor modulator raloxifene. Circulation 105 1368-1373... 

A number of compounds are capable of altering the rate of purine biosynthesis Je novo. Many that are capable of inhibiting purine biosynthesis Je novo appear to do so as a result of depletion of intracellular levels of PRPP (7). In most of these cases, the nucleotide derivative of the compound is formed and this derivative may also play a role in the inhibition of the PRPP amidotransferase and/or PRPP synthetase. Examples include adenine, allopurinol, 2 6-diaminopurine, nicotinic acid, and orotic acid. On the other hand, several compounds have been studied which lead to an acceleration in the rate of purine biosynthesis apparently mediated by an increased level of PRPP (7). Examples of this category might include fructose, methylene blue, ACTH, TSH, and estrogens. 

PP-ribose-P has been reported by others to be elevated by nucleosides and the trophic hormones, ACTH and TSH,which also presumably act by increasing ribose-5-P availability (Fox and Kelley, 1971). In addition. Estrogen has been observed to stimulate the synthesis of PP-ribose-P synthetase in rat uterus (Oliver, 1972). Finally, inhibition of PP-ribose-P hydrolysis provides a potential means of elevating intracellular PP-ribose-P levels (Fox and Marchant, in preparation). ... 

---