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Hydroxylated C18 and C19 Steroids; Their Significance and Factors Related to Their Biosynthesis
Published in Ronald Hobkirk, Steroid Biochemistry, 1979
The catechol estrogens structurally resemble epinephrine and norepinephrine in that they possess the o-quinol structure. These steroids are capable of competing with the catecholamines30,31 for the enzyme catechol-O-methyl transferase (EC 2.1.1.a) which plays an important role in the inactivation of the amines in question. This has led investigators to propose that the 2-hydroxy phenolic steroids, which lead to an increased half-life of the active amines, could be involved in the etiology of certain hypertensive disorders.32,33 A further relationship between this interesting class of steroids and the central nervous system (CNS) has arisen from the studies reported by Naftolin et al.34 in which subcutaneously administered 2-hydroxyestrone, but not estrone, caused a dramatic rise in serum LH in the immature male rat. In a separate study,35 it was found that either 2-hydroxyestrone or estrone could considerably stimulate both plasma LH and FSH in oophorectomized adult rats whose gonadotropin levels had been suppressed by priming with estradiol. It has also been claimed36 that 2-hydroxyestradiol [estra-1,3,5(10)-triene-2,3,17β-triol] led to a fall in plasma LH when introduced into the amygdala of orchidectomized minipigs. These data, as well as other findings of 2-hydroxylation of estrogens by CNS tissues from rat37 and human fetuses38 together with the presence of high-affinity binding sites for 2-hydroxyestrone and 2-hydroxyestradiol in high-speed supernatants of rat pituitary and anterior hypothalamus,39 point to important functions for the catechol estrogens.
Substrates of Human CYP2D6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
CYP2D6 can catalyze 2-hydroxylation of estrogens, although CYP1A1 and 1A2 have been considered as the major CYP enzymes responsible for the 2-hydroxylation of 17β-estradiol (Figure 3.117) and estrone (Figure 3.118) in extrahepatic tissues including breast (Lee et al. 2003). Subsequent metabolism of catechol estrogens involves catechol O-methyltransferase (COMT) and their conjugation by other Phase II enzymes. Under conditions of poor protection of catechol estrogens by Phase II enzymes, they can undergo oxidation to their reactive semiquinone and quinone derivatives, which has been postulated to be an initiating/promoting factor in estrogen-induced carcinogenesis (Yager and Liehr 1996). CYP1A1 forms more 4-hydroxyestrone than 15α- or 6α-hydroxyestrone. CYP1A2 has the highest activity for the 2-hydroxylation of both 17β-estradiol and estrone, although it also had considerable activity for their 4-hydroxylation (9%–13% of 2-hydroxylation) (Lee et al. 2003). CYP1B1 mainly catalyzes the formation of catechol estrogens, with 4-hydroxyestrogen primary metabolites. CYP2A6, 2B6, 2C8, 2C9, 2C19, and 2D6 show a varying degree of low catalytic activity for estrogen 2-hydroxylation, whereas CYP2C18 and 2E1 do not show any detectable estrogen-hydroxylating activity. CYP3A4 has a strong activity for the formation of 2-hydroxyestradiol, followed by 4-hydroxyestradiol and an unknown polar metabolite, and small amounts of 16α- and 16β-hydroxyestrogens are also formed. CYP3A5 has similar catalytic activity for the formation of 2- and 4- hydroxyestrogens (Lee et al. 2003). Notably, CYP3A5 has an unusually high ratio of 4- to 2-hydroxy-lation of 17β-estradiol or estrone. CYP3A7 has a distinct catalytic activity for the 16α-hydroxylation of estrone, but not 17β-estradiol, while CYP4A11 shows little catalytic activity for the metabolism of 17β-estradiol and estrone (Lee et al. 2003).
Breast Cancer
Published in Peter G. Shields, Cancer Risk Assessment, 2005
Christine B. Ambrosone, Kirsten B. Moysich, Helena Furberg
Catechol-O-methyltransferase (COMT) is one of several phase II enzymes involved in the conjugation and inactivation of catechol estrogens (144). Because there is evidence that catechol estrogens, particularly the 4-hydroxy catechol estrogen, may bind to DNA and result in DNA damage (145), the possible role of lower activity in the enzyme in relation to breast cancer risk is important. Several groups to date, all with conflicting results, have evaluated the role of the COMT genetic polymorphism in relation to breast cancer risk. Lavigne et al. (146) found that women who were postmeno-pausal had a greater than twofold increase in risk with the low activity alleles, but inverse associations were noted for premenopausal women with the same genotype. Thompson et al. (147) performed similar analyses and observed that, among premenopausal women with breast cancer, those with at least one low activity allele showed significantly increased risk (OR = 2.4, CI, 1.4–4.3). In contrast to premenopausal women, there was an inverse association between low activity alleles and postmenopausal breast cancer. Mitrunen et al. (148) noted inverse associations for women with low activity COMT alleles in relation to premenopausal breast cancer risk, and elevated associations for postmenopausal women, particularly those using exogenous estrogens or early age at menarche. The authors hypothesized that there may be an opposing role of catechol estrogen metabolism in breast cancer etiology depending on the hormonal environment. Yim et al. (149) also reported that the low activity COMT allele was associated with increased risk of breast cancer among Asian women. Millikan (150) and Bergman-Jungestrom (151), however, found no associations with COMT genotypes and increased breast cancer risk for pre- or postmenopausal women. These discrepancies may be due to small sample sizes in the previous studies, or there may be biological factors that differentially impact risk associations.
The WHO claims estrogens are ‘carcinogenic’: is this true?
Published in Climacteric, 2023
The production of both semiquinones as well as of quinones needs excessive oxidative cell stress (‘one-electron oxidation’) (i.e. additional factors) for carcinogenicity. Cells are equipped with extensive multifactorial antioxidative defenses, and additional environmental factors such as pollution or smoke, or additional exogenous factors (e.g. certain drugs, nutritional factors) are required for carcinogenicity, as already reported during the 1998 Conference of the US National Cancer Institute in Bethesda and published in Science [5]. Current research therefore focuses on whether this mechanism may be of special importance in certain areas of industrial pollution or in smokers where oxidative cell stress is increased. Increased hepatic activity in smokers leads to production of a higher amount of estrogen metabolites, which are precursors of potential toxic estrogen metabolites, as we described elsewhere [82]. Oral estrogen therapy in postmenopausal women can lead to an increase in 4-catechol estrogens compared to non-smokers, possibly leading to an increased breast cancer risk. This mechanism of cancer development can be avoided by using transdermal estradiol.
Tissue and interspecies comparison of catechol-O-methyltransferase mediated catalysis of 6-O-methylation of esculetin to scopoletin and its inhibition by entacapone and tolcapone
Published in Xenobiotica, 2021
Aaro Jalkanen, Veera Lassheikki, Tommi Torsti, Elham Gharib, Marko Lehtonen, Risto O. Juvonen
Catechol is an important chemical structural motif with multiple cellular functions. The catechol core structure consists of a benzene ring with two adjacent hydroxyl substituents. Humans are exposed to various types of endogenous and exogenous catechol compounds (Riishede and Nielsen-Kudsk 1990; Lekse et al.2001; Cavalieri et al.2006). Endogenous catechol compounds include 3,4-dihydroxytyrosine, catecholamines, their metabolites, catechol estrogens, and dihydroxyindole. Three catecholamines, i.e. dopamine, noradrenaline, and adrenaline, are synthesised from L-dopa, which is the product of the tyrosine hydroxylase oxidation of the amino acid, tyrosine. The catechol estrogens are CYP enzyme oxidisation products of estrogens such as estradiol, estrone, and estriol. Humans are also exposed to exogenous catechol compounds e.g. from therapeutic drugs containing the catechol moiety or from plant sources; in the latter, they protect the plant against UV-light, oxidants, herbivores, and microbes. Drugs containing the catechol core structure include isoprenaline, dobutamine, levodopa, droxidopa, benserazide, entacapone, tolcapone, and nitecapone. Phenolic drugs or other xenobiotics may be oxidised by CYPs to catechol compounds, as exemplified by traxoprodil (Johnson et al.2003) and duloxetine (Lantz et al.2003). Furthermore, plant constituents containing the catechol core structure include verbascoside (Reid et al.2019) and polyphenols such as tannins (Bianco and Savolainen 1994), catechins (Rhodes et al.2013), and flavonoids (Sak 2017).
Cheminformatics and virtual screening studies of COMT inhibitors as potential Parkinson’s disease therapeutics
Published in Expert Opinion on Drug Discovery, 2020
Kalliopi Moschovou, Georgia Melagraki, Thomas Mavromoustakos, Lefteris C. Zacharia, Antreas Afantitis
Lautala et al. showed that the electron withdrawing effect of substituents was the driving force in decrease of the turnover rate and the increase of affinity [25]. The unsubstituted catechol and pyrogallol had the highest turnover rates, and pyrogallol derivatives appeared to be more specific substrates than catechols. Catecholamines were rather poor substrates whereas catechol estrogens were more specific endogenous substrates. Further, the structure-activity relationships allowed the accurate affinity and specificity prediction with a variety of structures and properties [25] (Figure 2(a)).