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Dietary Phytoestrogens
Published in Rajesh K. Naz, Endocrine Disruptors, 2004
Heather B. Patisaul, Patricia L. Whitten
2-hydroxylated estrogens to the more genotoxic 4- and 16 α -hydroxylated forms are believed to be correlated with breast cancer risk.108,109 16α-Hydroxyestrogen (16α-OHE) induces DNA synthesis110 while 4-hydroxyestradiol (4-OHE2) and 4-hydroxyestrogen (4-OHE1) have been shown to generate mutations that initiate cancer.111 There is good evidence that isoflavones may significantly increase the ratio of 2-OH to both 16α-OHE and 4-OHE. Consumption of a dietary supplement containing at least 65 mg of isoflavones per day improved the 2- to 4-(OHE) ratio by 33% and the 2-to-16αOHE ratio by 67%, compared to a supplement containing only 10 mg of isoflavones.112 Other studies using isolated soy protein or soy milk have found similarly compelling effects,68,113 while at least one study using isolated soy protein delivering only 38 mg of isoflavones per day found only modest 7% increase in the 2–16αOHE ratio.69 Interestingly, urinary levels of 16α-OHE are only positively associated with urinary levels of isoflavones in equol-producing women, and within that group, the ratio of 16α-OHE to 2-OHE is significantly positively correlated to equol excretion, suggesting that this daidzein metabolite may be critical for this effect.114
Hydroxylated C18 and C19 Steroids; Their Significance and Factors Related to Their Biosynthesis
Published in Ronald Hobkirk, Steroid Biochemistry, 1979
With the exception of the 2- and 16-hydroxylated phenolic steroids, there is little information as to the biological function of the many hydroxylated forms known to be naturally occurring. The relationship of hydroxylation at any specific position of the steroid molecule to a particular biological function is unclear. Relatively recent evidence50 for the formation of 4-hydroxylated estrogens in the human (albeit in small amount), coupled with the information40 that 4-hydroxyestradiol [estra-1,3,5(10)-triene-3,4,17β-triol] is bound by rat uterine cytosol receptor to the extent of 43% that of estradiol (cf., 23% for 2-hydroxyestradiol), suggests an avenue for exploration. It has also been reported43 that 4-hydroxyestradiol stimulates formate incorporation into protein of rat and mouse uterine tissue in vitro to a much greater degree than does estradiol, although the latter hormone has ten times more uterotropic activity. Rat liver preparations are also known51 to form pyrogallolestrogens (i.e., 2,3,4-trihydroxy compounds) from the catechol estrogens. These, as well as certain of their methyl ethers, can inhibit the catechol-O-methyl transferase of rat liver.52 Thus, 4-hydroxylation may prove to be of some importance.
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).
The WHO claims estrogens are ‘carcinogenic’: is this true?
Published in Climacteric, 2023
The 4-hydroxy estrogens can stimulate growth of human breast cancer cells [63,64]. Relatively unstable, they can be transformed into highly reactive quinones with the formation of semiquinones as an intermediate stage [69] (Figure 2(a,b)) (see later section ‘Additive oxidative cell stress’). Adducts of DNA with 4-hydroxy estrogen quinones are unstable DNA compounds, which lead to destruction via depurination. DNA adducts with 2-hydroxy estrogen are more stable, and are reversible without DNA destruction [69,70]. Elevated 4-hydroxylase enzyme activity and 4-hydroxyestradiol were found in high concentrations in human breast cancer tissues [63,71,72]. Concentrations of quinones were higher in the cancer tissue compared to control [72]. Animal experiments clearly showed a mutagenic effect of 4-hydroxyestradiol quinones [73].
The effect of carbamazepine, which increases oestrogen destruction, on the endometriotic implants; an experimental rat model
Published in Journal of Obstetrics and Gynaecology, 2022
Mehmet Bulbul, Mehmet Can Nacar, Bilge Aydin Turk, Talip Karacor, Muhittin Onderci, Ali Parlar, Pınar Kirici, Cihat Ucar
Oestrogen acts on the body through itself and its metabolites. Although it has different metabolites, it is generally metabolised to 2-hydroxyestradiol by the CYP3A4 enzyme in the liver and peripheral tissues (Liehr and Ricci, 1996; Shou et al. 1997). Many studies have shown that 2-hydroxyestradiol can prevent cancer development (Fotsis et al. 1994; Klauber et al. 1997). In contrast, 4-hydroxyestradiol, another oestrogen metabolite, contributes to carcinogenesis through free oxygen radicals (Lemon et al. 1992; Nutter et al. 1994; Liehr and Ricci, 1996). CMZ is known to decrease the efficiency of contraceptives by increasing CYP3A4 activity—hence, oestrogen degradation (Gaffield et al. 2011; Guillemette and Yount, 2012; Reimers et al. 2015; Herzog et al. 2016; Reddy 2017, 2010; Hole et al. 2018; Lutz et al. 2018; Ke et al. 2019). With this effect of CMZ, oestradiol levels in target tissues decrease and 2-hydroxyestradiol levels increase. This change in oestradiol/2-hydroxyestradiol balance may protect the target tissues against the adverse effect of oestrogen. In our study, endometrial hyperplasia developed in three rats in the EV group, but no endometrial hyperplasia formation was found in the EV + CMZ group, supporting this information.
Two-sided role of estrogen on endometrial carcinogenesis: stimulator or suppressor?
Published in Gynecological Endocrinology, 2019
Tsutomu Miyamoto, Tanri Shiozawa
Malignant transformation tends to occur in actively proliferating cells because DNA replication errors accumulate during DNA duplication and mitosis [10]. Therefore, E2 is potentially carcinogenic to NEG cells. Although E2 itself is not carcinogenetic, catechol estrogen such as 4-hydroxyestradiol, a metabolite of E2, is reportedly genotoxic and carcinogenic in animal models [28]. We reported that 4-hydroxyestradiol induces DNA damage on codon 130/131 of PTEN in EC cells [29]. However, actual tissue concentrations of these metabolites have not been measured in normal and carcinomatous endometria, and the levels of estrogen metabolites are shown to be generally low when the parent E2 level is low [30]. It should be noted that the dependency of carcinogenicity on E2 metabolism is complex, with follow up reactions within the cells. Therefore, E2 levels are sometimes less representative for this risk.