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Transdermal estrogen therapy and the risk of breast cancer: a clinical appraisal
Published in A. R. Genazzani, Hormone Replacement Therapy and Cancer, 2020
Estrogen catabolism takes place in two stages: hydroxylation and methylation (Figure 1). Estrone and estradiol are hydroxylated to the following: 2-hydroxyestrone (2-OHE1); 2-hydroxyestradiol (2-OHE2); 4-hydroxyestrone (4-OHE1); 4-hydroxyestradiol (4-OHE2); 16-hydroxyestrone (16-OHE1); and 16-hydroxyestradiol (16-OHE2). The 2-hydroxy estrogens are referred to as the A-ring metabolites, and 16-hydroxy estrogens as the D-ring metabolites. The D-ring metabolites are bioavailable and estrogenic. Women who preferentially metabolize their endogenous estrogens via the 16a-hydroxylation pathway (versus 2α-hydroxylation) are at higher risk of breast cancer9. The hydroxylation of estrogen is genetically controlled; for example, the CYP1A1 gene, which encodes cytochrome p450 1A1, inhibits or downgrades the activity of the 2<x-hydroxy pathway, thereby diminishing the concentration of the benign protective 2-hydroxy estrogens in favor of the biologically potent 16-hydroxyestradiol metabolite10.
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).
Inhibition of UDP-glucuronosyltransferases by different furoquinoline alkaloids
Published in Xenobiotica, 2020
Yixuan Li, Weihua Zhang, Tingting Yin, Ce Wang, Feige Wang, Jing Sun, Lina Liu, Qinghuai Zhang, Chunze Zhang
Furthermore, a large number of studies have shown dictamnine produced hepatotoxicity via metabolic activation by CYP3A4 in vivo (Douros et al., 2016; Shi et al., 2019). This study provides another possibility for liver damage caused by dictamnine. It might be related to the furan ring structure and the inhibition of UGTs. UGTs maintained the metabolic balance by participating in the metabolic elimination of endogenous substances. Under pathological conditions, the concentration of bile acids in the blood increases and produces toxicity. UGT1A3 and UGT2B4 are involved in the metabolism of bile acids and play important roles in a defensive mechanism, preventing bile acids cytotoxicity (Barrett et al., 2015). UGT1A9 is responsible for glucuronidation of many endogenous substances, such as 4-hydroxyestrone, acetylenic estrone and thyroxine (Liu et al., 2016). Meanwhile, many drugs with hepatotoxicity are related to the inhibition of UGT1A9. For example, defective glucuronidation activity of UGT1A9 has been claimed to be the cause of catechol-O-methyltransferase inhibitor-induced hepatic dysfunction (Martignoni et al., 2005). Inhibition of UGT1A9 activity has been identified as a potential mechanism of emodin and paracetamol hepatotoxicity (Liu, Ramirez, et al., 2011; Wu et al., 2018). Reduced activity of UGT1A9 often induces hepatotoxicity. Therefore, the strong inhibition of dictamnine and γ-fagarine towards UGT1A3 and UGT1A9 should be given much attention.
The WHO claims estrogens are ‘carcinogenic’: is this true?
Published in Climacteric, 2023
The main primary metabolites formed by A-ring metabolism are 2-hydroxyestrone and 4-hydroxyestrone, and by D-ring metabolism are 16α-hydroxyestrone (16-OH-E1) and estriol (Figure 1(a)). Most primary estrogen metabolites undergo an additional degradation step by conjugation, either by glucuronidation, sulfation or methylation.