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Environmental Toxins and Chronic Illness
Published in Aruna Bakhru, Nutrition and Integrative Medicine, 2018
One phase II methylation enzyme, in particular, has received much attention in the research and clinical communities because of its involvement in metabolism of estrogen metabolites that may promote breast cancer formation. During phase I metabolism estradiol (E2) is metabolized to the strongly procarcinogenic compound 4-hydroxy-estradiol (4-OH-E2) (Zhu, 2003). Fortunately, the adverse impact on health of this metabolite is greatly minimized by the phase II methylation enzyme catechol-O-methyltransferase (COMT), which converts 4-OH-E2 to the relatively inert O-methylated metabolite 4-methoxyestradiol (4-MeO-E2) (Zhu, 2003). However, the anticarcinogenic properties of COMT do not end here. COMT also converts 2-hydroxyestradiol (2-OH-E2) to 2-methoxyestradiol (2-MeO-E2) (Zhu, 2003). 2-MeO-E2 is associated with reduced cancer formation in several ways. First, it has little or no estrogen receptor-binding activity. Next, it may actually prevent cancer formation due to its antiproliferative, cytotoxic, and apoptotic actions (Zhu, 2002).
Effects of xenobiotics on CYP1 enzyme-mediated biotransformation and bioactivation of estradiol
Published in Drug Metabolism Reviews, 2023
CYP1-mediated biotransformation of E2 has been systematically investigated in recent years. Oxidative hydroxylation is the first step of its biochemical reaction. The major hydroxylation has been observed to occur at C-2 and C-4 of the aromatic ring both in vitro and in vivo (Lee et al. 2003; Dallal et al. 2014). CYP1A1 and CYP1A2 dominantly catalyze the formation of 2-OH-E2, while CYP1B1 specifically catalyzes the formation of 4-OH-E2 (Lee et al. 2003; Tsuchiya et al. 2005; Niwa et al. 2015), as shown in Scheme 1. 4-OH-E2 has been identified as a reactive estrogen metabolite. Except for a little conversion to nontoxic 4-methoxyestradiol (4-CH3O-E2) by catechol-O-methyltransferase (COMT), the majority of 4-OH-E2 is peculiarly prone to be bioactivated to estrodial-3,4-quinone (E2-3,4-Q). E2-3,4-Q is a known electrophile that can covalently bind to adenine and/or guanine bases in DNA by nucleophilic addition reaction to generate DNA adducts (4-OH-E2-1-N3Ade and 4-OH-E2-1-N7Gua), thereby triggering E2-associated cancers (Yue et al. 2003; Huang et al. 2011). Meanwhile, E2-3,4-Q can be also reduced to the corresponding semiquinone (estrodial-3,4-semiquinone, E2-3,4-SQ) by cytochrome P450 reductase, and reactive oxygen species (ROS) resulting from redox cycling of quinone and semiquinone intermediates further cause oxidative DNA damage in this metabolic process (Yue et al. 2013; Blackburn et al. 2015; Yager 2015). ROS served as an initiator of cancer may facilitate mutagenesis and tumor progression as well (Agostinelli and Seiler 2006). It has been found that administration of E2 or 4-OH-E2 induced tumorigenesis in mice (Tsuchiya et al. 2005; Takemura, Uchiyama, et al. 2010). Elevated levels of 4-OH-E2 and DNA adducts have also been detected in human E2-associated tumors (Tsuchiya et al. 2005; Zahid et al. 2019). Unlike 4-OH-E2, the less reactive 2-OH-E2 is more readily O-methylated to nontoxic 2-methoxyestradiol (2-CH3O-E2) by COMT, followed by elimination from the body (Yue et al. 2003; Huang et al. 2011). Studies have shown that increased 2-pathway metabolites were linked to a lower cancer risk (Ziegler et al. 2015; Moore et al. 2016). 2-CH3O-E2, an estrogenically inactive metabolite, has been proven to effectively promote apoptosis of fast-growing tumor cells, which is expected to be a potent anti-cancer drug (Lakhani et al. 2003; Schwarz et al. 2011; Peyrat et al. 2012). Additionally, elevated 4-OH-E2/2-OH-E2 formation rates have been obviously observed in estrogenic tumor tissues than in normal tissues (Takemura, Uchiyama, et al. 2010). Hence, 4-OH-E2 and 2-OH-E2 can be regarded as carcinogenic and detoxifying biomarkers of E2, respectively. The specificity and local generation of 4-OH-E2 are crucial for the carcinogenesis of E2.