2-Hydroxyestradiol Is a Prodrug of 2-Methoxyestradiol

Abstract

Previous in vivo studies indicate that 2-hydroxyestradiol (2OHE) attenuates cardiovascular and renal diseases. In vitro studies suggest that the biological effects of 2OHE are mediated by 2-methoxyestradiol (2MEOE) after methylation of 2OHE by catechol-O-methyltransferase (COMT). This study tested the hypothesis that in vivo 2OHE is a prodrug of 2MEOE. We administered to male rats i.v. boluses of either 2OHE or 2MEOE and measured plasma levels of 2OHE and 2MEOE by gas chromatography-mass spectrometry at various time points after drug administration. After administration of 2OHE, plasma levels of 2OHE declined extremely rapidly [t 1/2(1) ϭ 0.94 min and t 1/2(2) ϭ 10.2 min] becoming undetectable after 45 min. Concomitant with the disappearance of 2OHE, 2MEOE occurred and then declined [t 1/2(1) ϭ 7.9 min and t 1/2(2) ϭ 24.9 min]. The peak concentration and total exposure (area under the curve) for 2OHE were much lower than for 2MEOE. 2OHE had a much higher plasma clearance (CL) and volume of distribution (V d ) compared with 2MEOE (2OHE: CL ϭ 1215 ml min Ϫ1 kg Ϫ1 and V d ϭ 17,875 ml/kg; 2MEOE: CL ϭ 50 ml min Ϫ1 kg Ϫ1 and V d ϭ 1760 ml/kg). After administration of 2MEOE, plasma levels of 2MEOE declined [t 1/2(1) ϭ 2.5 min and t 1/2(2) ϭ 20.2 min] with a plasma CL of 50 ml min Ϫ1 kg Ϫ1 and a V d of 1500 ml/kg. We could not detect 2OHE in plasma from rats receiving 2MEOE. We conclude that the conversion of 2OHE to 2MEOE is so efficient that in terms of 2MEOE exposure, administration of 2OHE is bioequivalent to administration of 2MEOE itself.2-Hydroxyestradiol (2OHE) is a metabolite of estradiol with low affinity for estrogen receptors (Ball and Knuppen, 1990). Our in vivo work demonstrates that 2OHE attenuates the development of obesity, the metabolic syndrome, and vascular and renal dysfunction in obese ZSF1 rats (Tofovic et al., 2001). Moreover, our more recent studies indicate that 2OHE protects against puromycin aminonucleoside-induced nephropathy (Tofovic et al., 2002), monocrotaline-induced pulmonary hypertension (Tofovic et al., 2003b), and angiotensin II-induced renal and cardiovascular injury (Tofovic et al., 2003a).Although the aforementioned in vivo studies were conducted with 2OHE, in point-of-fact 2OHE is readily oxidized and is therefore a poor candidate for drug development. 2-Methoxyestradiol (2MEOE), on the other hand, is less susceptible to oxidation, and in vitro evidence suggests that most of the cellular effects of 2OHE are mediated by 2MEOE, a metabolite of 2OHE that is devoid of estrogenic activity. In this regard, inhibition of catechol-O-methyltransferase (COMT), the enzyme that methylates 2OHE and converts it to 2MEOE, blocks the ability of 2OHE to inhibit growth of vascular smooth muscle cells (Dubey et al., 2000), cardiac fibroblasts (Dubey et al., 2002b), and renal mesangial cells (Dubey et al., 2002a). Moreover, 2OHE inhibits vascular smooth muscle cell growth in cells obtained from wild-type mice but not in cells cultured from COMT knockout mice (Zacharia et al., 2003b). In cont...

Therapeutic Promises of 2-Methoxyestradiol and Its Drug Disposition Challenges

“…However, no determinations of 2MeO-E2 distribution in mice intestine were performed, although this organ could be vital in 2MeO-E2 metabolism. PK analysis has shown that 2MeO-E2 elimination followed a biexponential pattern with a terminal half-life (t ½ ) of 19 minutes, which was in agreement with the findings of other investigators, t 1/2 of 14 and 20.2 minutes 33,34. 2MeO-E2 clearance (CL) and volume distribution (V d ) were estimated to be 0.36 or 14.3 ml/min and volume of distribution of 52.9 or 427.5 ml for mice and rats, respectively.…”

Effect of 2-hydroxyestradiol on binge intake in rats

“…That is, in week 1, shortening was available to the rats for one hour; in week 2 it was available for 40 minutes, and for all subsequent weeks it was available for 20 minutes. The shortening availability was limited to 20 minutes in this study due to the relatively short half-life of 2OHE2 (t 1/2(1) =0.54 min, t 1/2(2) =10 min) [16]. …”

Estrogens and atherosclerosis: insights from animal models and cell systems

“…For instance, 2-methoxyestradiol (2-ME), which is the major metabolite of E 2 formed via sequential conversion of E 2 to 2-hydroxyestradiol and 2-ME by cytochrome P450 and catechol-O-methyltransferase (COMT) and is produced in various tissues in addition to ovary (Zacharia et al 2004), was demonstrated to attenuate atherosclerosis in female Apoe KO mice (Bourghardt et al 2007). Similar favorable effects were also seen after administration of isoflavones exerting weak estrogenic effects (Adams et al 2002a,b).…”