Here we go:--High concentrations The physiologic role of this interaction remains uncertain.
Catechol estrogens have been shown to be potent inhibitors of the COMT-mediated
Action 1:-catechol oestrogens cause Inactivation of catecholamines. Since catechol estrogens exhibit high affinities for the estrogen receptor protein, it is assumed that the Action 2:-
majority of their non-DNA reactive activities are mediated in a mechanism similar to that evoked by ovarian estrogens.
Mode of action:-The catechol estrogen A) bound estrogen receptors to recruit coactivators and corepressor proteins, recent evidence clearly suggests the most active catechol estrogens
B)alter gene expression in certain target cells.
C) Catechol estrogens are generated by the actions of genes encoded by CYP1A1 and CYP1A2 (which catalyze 2-hydroxylation of estrogens), and CYP1B1, which is an estrogen 4-hydroxylase..
Although the catechol estrogens are short-lived in vivo and are postulated to have physiological functions as locally generated signaling molecules, they also yield potent genotoxic molecules implicated in carcinogenesis. The 4-hydroxyestrogens can be oxidized to quinone intermediates that react with purine bases of DNA, resulting in depurinating adducts that generate highly mutagenic apurinic sites .
Quinones derived from the 2-hydroxyestrogens produce stable DNA adducts and are presumed to be less genotoxic. Metabolism of catechol estrogens may also generate oxygen-free radicals.
Catechol estrogens are methylated by catechol-O-methyltransferase, resulting in a catecholamine-like substance. The methylated catechol estrogens have antiangiogenic and antitumor activity through inhibition of hypoxia-inducible factor-1α (HIF-1α), a proangiogenic transcription factor. There is evidence that altered production of 2-methoxyestradiol may contribute to the pathogenesis of preeclampsia through its modulation of antiangiogenic factor production by the placenta.
Catecholestrogens, an important group of estrogen metabolites which possess significant endocrine properties of their own, are synthesized in brain, liver and other tissues by estrogen-2 hydroxylase, a cytochrome-P450 dependent monooxygenase. Estrogen-2-hydroxylase activity can be detected in both liver and brain in the fetal rat.
By eight weeks of age, sexual dimorphism is apparent: male rats have higher specific enzyme activities in both liver and brain than female rats.
Androgenic hormones play a crucial role in the expression of enzyme activity in the adult animal. In utero exposure to phenobarbital results in substantial changes in brain and liver estrogen-2-hydroxylase activities during the first three weeks of life.
Potential Safety Problems
COMT inhibitors may change the metabolism of endogenous catechol products, such as catecholamines and catechol estrogens (Männistö and Kaakkola, 1999). Concerning catecholamines no relevant safety problems have been associated with COMT inhibitors (Kaakkola, 2000). The effect of COMT inhibitors on catechol estrogen metabolism is still poorly studied and known in humans. Catechol estrogens may be involved in, e.g., some hormonal-dependent cancer formation (Creveling, 2003; Zhu, 2002). So far, no data are available that COMT inhibitors increase or decrease cancer incidence in PD patients. In a recent study in PD patients treated with entacapone slightly more prostate cancer cases were observed in an active drug group compared with a placebo group (Stocchi et al., 2010). In earlier entacapone studies this phenomenon has not observed. Another theoretical safety issue may be related to levodopa metabolism when both DDC and COMT pathways are effectively blocked (Fig. 2). There is a risk that the amount of dopa quinone metabolite increases. This metabolite is labile and potentially toxic, e.g., to dopaminergic cells (Kostrzewa et al., 2002). This concern is probably more relevant if brain COMT is effectively inhibited.
EFFECTS ON CATECHOLAMINE TURNOVER
As mentioned above, their interference in catecholamine metabolism is one of the most widely discussed features of catecholestrogens in the brain. To estimate the degree of such interference, we measured dopamine, norepinephrine and epinephrine concentrations and turnover rates in response to 2-hydroxyestradiol-17β and 2-hydroxyestrone (2-OHE1) in adult orchidectomized and adult ovariectomized rats.
Intramuscular injections of 2-OHE2 and 2-OHE1 (50 ng) or their solvent were given at 1000 h. Females received injections on two subsequent days. α-Methyl-paratyrosinemethylester (250 mg free base/kg) was injected i p at 1400 h to block synthesis of catecholamines. The animals, 10 each group, were rapidly killed by decapitation at 1400 h or at I5OO h. The brains were removed immediately and frozen on dry ice. Trunk blood was collected for assay of LH and prolactin. Medial preoptic area (MPO) and the anterior part of the hypothalamus (AMBH) were punched from 0.8 to 1.0 mm thick frozen slices with sharpened needles. The brain tissues were then handled as described by Höhn and Wuttke (1978). Turnover rates were calculated as described by Brodie and colleagues (1966).
In the male 2-OHE2 and 2-OHE1 decreased serum LH levels but had no effect on prolactin secretion. In the females only 2-OHE2 was effective in altering serum hormone levels. It decreased the level of LH and increased the level of prolactin. It seems not surprising that 2-OHE1 had no sigExploring the unknown!!! Catechol amines are partly known to us but do we, the practicing gynaecologits are aware anything what is called as Catechol oestrogens??
nificant effects in females, since other investigators
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