Interactions Between Estrogens and Catechol Amines III. Studies on the Methylation of Catechol Estrogens, Catechol Amines and other Catechols by the Catechol-O-Methyltransferase1 of Human Liver

Abstract

The substrate specificity of the catechol-O-methyltransferase, purified from human liver 380-fold, has been tested with a variety of compounds. Cateehol estrogens, as well as cateehol amines are methylated to their corresponding monomethyl ethers. The relation of the rates of methylation of cateehol estrogens and cateehol amines depended on enzyme and substrate concentration; under standard assay conditions, 2-hydroxy-17P-estradiol was the preferred substrate for the enzyme, as compared with epinephrine and other catechols tested. K m -values for 2-hydroxy-17P-estradiol were 15 M*M, for 2-hydroxy-estrone 20 M-M, for 2-hydroxy-estriol 25 M^M and for 4-hydroxy-estrone 20 M-M. For epinephrine and norepinephrine, K m -values of 300 M-M and 200 \IM, respectively, were obtained. The ratio of formation of the isomeric monomethyl ethers of cateehol estrogens varied between 1.3 and 95, depending on the substrate incubated. On the basis of kinetic studies with different enzyme preparations, different inhibitors and different concentrations of the substrates, it is concluded that both cateehol estrogens and cateehol amines are methylated by the same catechol-O-methyltransferase. The enzymic methylation of epinephrine was inhibited competitively by 2-and 4-hydroxylated estrogens; the K,-values were 7.0 M-M for 2-hydroxy-17P-estradiol, 8.5 M-M for 2-hydroxy-estrone, 12.2 M-M for 2-hydroxy-estriol, 50 M-M for 4-hydroxy-estrone and, for comparison, 154 M-M for the addition of norepinephrine. A non-competitive inhibition was observed with the corresponding isomeric monomethyl ethers. The extent of inhibition not only depended on the relative concentrations of substrates and inhibitors, but also on the concentrations of MgClo, 5-adenosylmethionine and enzyme.The results reported here indicate that the enzymic methylation and biological inactivation of neurotransmitters is strongly inhibited by 2-hydroxy-estrogens. These findings are of possible clinical relevance with respect to the regulation of blood pressure under normal and pathological conditions. (/ Clin Endocr 34: 736, 1972)

Aromatase and Estrogen 2-Hydroxylase Activities of Human Placental Microsomes in Pregnancy-Induced Hypertension.

“…The ratio of aromatase to estrogen 2-hydroxylase activity in PIH placentas was also higher than that in normal placentas. It has been reported that the 2-hydroxyestrogens can modify the action of catecholamines by inhibiting COMT and a relationship between catechol estrogen metabolism and PIH [9][10][11] has been suggested. Gelbke et al [6] showed that the administration of 20 mg of estrone increased systolic and diastolic blood pressure 1 h after the injection at which time the maximal increase in 2-methoxyestrone levels in serum was observed.…”

“…They also confirmed that both activities were exhibited in Chinese hamster ovarian cells transfected with human placental aromatase cDNA, pH /3-Aro. On the other hand, it has been suggested that the effect of catechol estrogens on human placental steroidogenesis may be related to pregnancy-induced hypertension (PIH) because of evidence indicating that the catechol estrogens can modify the action of catecholamines by inhibiting of catechol-0-methyltransf erase (COMT) as competitive inhibitors [9][10][11]. However, the metabolism and physiological significance of catechol estrogens have not yet been determined completely.…”

Differential effects of 16α-hydroxyestrone and 2-methoxyestradiol on cyclin D1 involving the transcription factor ATF-2 in MCF-7 breast cancer cells

“…Increased 16 -hydroxylation in women is associated with increased breast cancer risk (Muti et al 2000). 16 -Hydroxylated metabolites stimulate breast cancer cell growth, whereas the 2-hydroxylated estrogens inhibit cell growth (Ball et al 1972, Seegers et al 1989, Lottering et al 1992, Zhu & Conney 1998. 2-OHE 1 and 2-OHE 2 are rapidly converted to the monomethyl ethers, 2-ME 1 and 2-ME 2 respectively by the enzyme catechol-O-methyltransferase (COMT) (Ball et al 1972, Jefcoate et al 2000.…”

“…16 -Hydroxylated metabolites stimulate breast cancer cell growth, whereas the 2-hydroxylated estrogens inhibit cell growth (Ball et al 1972, Seegers et al 1989, Lottering et al 1992, Zhu & Conney 1998. 2-OHE 1 and 2-OHE 2 are rapidly converted to the monomethyl ethers, 2-ME 1 and 2-ME 2 respectively by the enzyme catechol-O-methyltransferase (COMT) (Ball et al 1972, Jefcoate et al 2000. 2-ME 2 inhibits the growth of human mammary cancer cells in vitro and in vivo (Lottering et al 1992, Fotis et al 1994.…”

Genomic organization of the human catechol O‐methyltransferase gene and its expression from two distinct promoters

“…COMT has a role in the biosynthesis of melanin (Pavel, 1993) and several investigators have postulated the involvement of this enzyme in such human mental disorders as depression and schizophrenia (Murphy and Wyatt, 1975). COMT also inactivates L-Dopa, a catechol-containing drug used as a dopamine precursor in the treatment of Parkinson's disease (Ball et al, 1972;Guldberg and Marsden, 1975). Due to its harmful effect on the medication of Parkinson's disease, a great deal of interest has been directed towards the development of specific COMT inhibitors (Guldberg and Marsden, 1975 ;Mannisto and Kaakkola, 1989) and the determination of the structure of the enzyme itself.…”