Characterization of the Oxidative Metabolites of 17β-Estradiol and Estrone Formed by 15 Selectively Expressed Human Cytochrome P450 Isoforms

Abstract

We systematically characterized the oxidative metabolites of 17beta-estradiol and estrone formed by 15 human cytochrome P450 (CYP) isoforms. CYP1A1 had high activity for 17beta-estradiol 2-hydroxylation, followed by 15alpha-, 6alpha-, 4-, and 7alpha-hydroxylation. However, when estrone was the substrate, CYP1A1 formed more 4-hydroxyestrone than 15alpha- or 6alpha-hydroxyestrone, with 2-hydroxyestrone as the major metabolite. CYP1A2 had the highest activity for the 2-hydroxylation of both 17beta-estradiol and estrone, although it also had considerable activity for their 4-hydroxylation (9-13% of 2-hydroxylation). CYP1B1 mainly catalyzed the formation of catechol estrogens, with 4-hydroxyestrogens predominant. CYP2A6, 2B6, 2C8, 2C9, 2C19, and 2D6 each showed a varying degree of low catalytic activity for estrogen 2-hydroxylation, whereas CYP2C18 and CYP2E1 did not show any detectable estrogen-hydroxylating activity. CYP3A4 had strong activity for the formation of 2-hydroxyestradiol, followed by 4-hydroxyestradiol and an unknown polar metabolite, and small amounts of 16alpha- and 16beta-hydroxyestrogens were also formed. The ratio of 4- to 2-hydroxylation of 17beta-estradiol or estrone with CYP3A4 was 0.22 or 0.51, respectively. CYP3A5 had similar catalytic activity for the formation of 2- and 4- hydroxyestrogens. Notably, CYP3A5 had an unusually high ratio of 4- to 2-hydroxylation of 17beta-estradiol or estrone (0.53 or 1.26, respectively). CYP3A4 and 3A5 also catalyzed the formation of nonpolar estrogen metabolite peaks (chromatographically less polar than estrone). CYP3A7 had a distinct catalytic activity for the 16alpha-hydroxylation of estrone, but not 17beta-estradiol. CYP4A11 had little catalytic activity for the metabolism of 17beta-estradiol and estrone. In conclusion, many human CYP isoforms are involved in the oxidative metabolism of 17beta-estradiol and estrone, with a varying degree of catalytic activity and distinct regioselectivity.

Coffee prevents early events in tamoxifen-treated breast cancer patients and modulates hormone receptor status

“…Moreover, CYP1A2 is a key enzyme in the 2-hydroxylation of estrone and estradiol [36], in the metabolism of caffeine [37], and it contributes to tamoxifen metabolism [15]. CYP2C8/9 also contributes to the metabolism of caffeine [17] and tamoxifen [16].…”

Az ösztrogénmetabolom biológiai és klinikai jelentősége lokális folyamatokban

“…Ezek közül a legjelentősebb a máj P450-aktivitásának 10-15%-át kitevő CYP1A2, amely elsősorban a 2-es, jóval kisebb mértékben a 4-es pozícióban történő hidroxiláci-ót katalizálja [1,11]. Emellett számos egyéb, a CYP1-, CYP2-és CYP3-csoportokba tartozó enzim aktivitását igazolták (2. ábra).…”

“…Ezek közül csak egy az E3, emellett azonban 2-, 4-, 6α-, 6β-, 7α-, 12β-, 15α-, 15β-, 16α-és 16β-hidroxiláció útján, valamint epimerizációval is keletkeznek termékek [1,2]. E vegyületeknek hormonális, immunrendszeri működést, anyagcserét és malignus folyamatokat moduláló hatása van, amit alátámaszt, hogy az autoimmun betegségek előfordulási gyakorisága nemi preferenciát mutat, illetve, hogy a nők életciklusának kü-lönböző pontjain az ösztrogénháztartás a különböző szövetekben változik [3,4].…”

Coffee intake and CYP1A2*1F genotype predict breast volume in young women: implications for breast cancer

“…Some studies (Vatten et al, 1990;Baker et al, 2006;Nkondjock et al, 2006;Ganmaa et al, 2008), but not all (Rosenberg et al, 1985;Vatten et al, 1990;McLaughlin et al, 1992;Stensvold and Jacobsen, 1994;Michels et al, 2002), have reported that moderate-to-high coffee consumption protects against breast cancer, though a mechanism is unknown. None of these studies took CYP1A2*1F into account.Coffee is metabolised by the CYP1A2 enzyme, which also plays a key role in oestrogen metabolism (Le Marchand et al, 1997;Lee et al, 2003). Coffee contains not only caffeine but also phytooestrogens that can interact with and even block the oestrogen receptor (Magee and Rowland, 2004).…”

“…Coffee is metabolised by the CYP1A2 enzyme, which also plays a key role in oestrogen metabolism (Le Marchand et al, 1997;Lee et al, 2003). Coffee contains not only caffeine but also phytooestrogens that can interact with and even block the oestrogen receptor (Magee and Rowland, 2004).…”