Some new aspects of 17α-estradiol metabolism in man

Hobe, G; Schön, R; Goncharov, N. P.; Katsiya, G. V.; Koryakin, M. V.; Gesson-Cholat, Isabelle; Oettel, M; Zimmermann, Holger

doi:10.1016/s0039-128x(02)00058-2

Cited by 37 publications

(37 citation statements)

References 22 publications

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“…17aE2 is readily conjugated into various forms in humans (Hobe et al. 2002), and understanding the metabolism of this steroid may be important when considering translational potential of this drug to humans.…”

Section: Discussionmentioning

confidence: 99%

Male lifespan extension with 17‐α estradiol is linked to a sex‐specific metabolomic response modulated by gonadal hormones in mice

et al. 2018

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SummaryLongevity in mammals is influenced by sex, and lifespan extension in response to anti‐aging interventions is often sex‐specific, although the mechanisms underlying these sexual dimorphisms are largely unknown. Treatment of mice with 17‐α estradiol (17aE2) results in sex‐specific lifespan extension, with an increase in median survival in males of 19% and no survival effect in females. Given the links between lifespan extension and metabolism, we performed untargeted metabolomics analysis of liver, skeletal muscle and plasma from male and female mice treated with 17aE2 for eight months. We find that 17aE2 generates distinct sex‐specific changes in the metabolomic profile of liver and plasma. In males, 17aE2 treatment raised the abundance of several amino acids in the liver, and this was further associated with elevations in metabolites involved in urea cycling, suggesting altered amino acid metabolism. In females, amino acids and urea cycling metabolites were unaffected by 17aE2. 17aE2 also results in male‐specific elevations in a second estrogenic steroid—estriol‐3‐sulfate—suggesting different metabolism of this drug in males and females. To understand the underlying endocrine causes for these sexual dimorphisms, we castrated males and ovariectomized females prior to 17aE2 treatment, and found that virtually all the male‐specific metabolite responses to 17aE2 are inhibited or reduced by male castration. These results suggest novel metabolic pathways linked to male‐specific lifespan extension and show that the male‐specific metabolomic response to 17aE2 depends on the production of testicular hormones in adult life.

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Section: Discussionmentioning

confidence: 99%

Male lifespan extension with 17‐α estradiol is linked to a sex‐specific metabolomic response modulated by gonadal hormones in mice

et al. 2018

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“…After p.o. administration most of the epiestradiol is rapidly conjugated (Hobe et al, 2002), and conjugated forms of ␤-estradiol are readily detectable in blood (Raftogianis et al, 2000). In estrogen target tissues, such as breast, ␤-estradiol is extensively converted by cytochrome P450, catechol-O-methyltransferase, sulfotransferases, and UGT enzymes before being released into the circulation .…”

mentioning

confidence: 99%

The Configuration of the 17-Hydroxy Group Variably Influences the Glucuronidation of β-Estradiol and Epiestradiol by Human UDP-Glucuronosyltransferases

Itaaho¹,

Mackenzie²,

Ikushiro³

et al. 2008

Drug Metab Dispos

103

110

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ABSTRACT:The glucuronidation of 17␤-estradiol (␤-estradiol) and 17␣-estradiol (epiestradiol) was studied to elucidate how the orientation of the 17-OH group affects conjugation at the 3-OH or the 17-OH of either diastereomer. Recombinant human UDP-glucuronosyltransferases (UGTs) UGT1A1, UGT1A3, UGT1A7, UGT1A8, and UGT1A10 conjugated one or both diastereomers, mainly at the 3-OH. The activity of UGT1A4 was low and unique because it was directed merely toward the 17-OH of both aglycones. UGT1A10 exhibited particularly high estradiol glucuronidation activity, the rate and affinity of which were significantly higher in the case of ␤-estradiol than with epiestradiol. UGT1A9 did not catalyze estradiol glucuronidation, but UGT1A9-catalyzed scopoletin glucuronidation was competitively inhibited by ␤-estradiol. UGT2B4, UGT2B7, and UGT2B17 exclusively conjugated the estradiols at the 17-OH position in a highly stereoselective fashion. UGT2B4 was specific for epiestradiol; UGT2B7 glucuronidated both diastereomers, with high affinity for epiestradiol, whereas UGT2B17 only glucuronidated ␤-estradiol. UGT2B15 glucuronidated both estradiols at the 3-OH, with a strong preference for epiestradiol. Human UGT2A1 and UGT2A2 glucuronidated both diastereoisomers at both hydroxyl groups. Microsomal studies revealed that human liver mainly yielded epiestradiol 17-O-glucuronide, and human intestine primarily yielded ␤-estradiol 3-O-glucuronide, whereas rat liver preferentially formed ␤-estradiol 17-O-glucuronide. Of the three recombinant rat UGTs that were examined in this study, rUGT2B1 was specific for the 17-OH of ␤-estradiol, rUGT2B2 did not catalyze estradiol glucuronidation, whereas rUGT2B3 exhibited high activity toward the 17-OH in both diastereoisomers. The results show that although many UGTs can catalyze estradiol glucuronidation, there are marked differences in their kinetics, regioselectivity, and stereoselectivity.

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“…The method of acid solvolysis was modified by Tang and Crone [20] and Hobe et al [21]. In the acid solvolysis procedure, 1 M anhydrous HCl methanol/ethyl acetate solution was prepared by adding 7.11 mL of acetyl chloride to 40.5 mL of methanol (1:5.7, v/v), which was magnetically stirred and cooled in an ice-water bath, then 52.4 mL of ethyl acetate were added to the mix solution.…”

Section: Acid Solvolysismentioning

confidence: 99%

Simultaneous Analysis of Natural Free Estrogens and Their Sulfate Conjugates in Wastewater

Liu

Kanjo

Mizutani

2010

CLEAN Soil Air Water

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Natural estrogens from humans increasingly attract attention because of their strong endocrine disrupting potency. The discharge of sewage water is considered as the most important source of these endocrine disrupting chemicals (EDCs) in the environment. Therefore, a GC-MS method was developed for the simultaneous analysis of six natural free estrogens and their sulfate conjugates in municipal wastewater, in which natural free estrogens and sulfate conjugates were successfully separated from an Oasis HLB solid phase extraction (SPE) cartridge with two different eluents, and the sulfate conjugates were then transformed to their corresponding free estrogens by acid solvolysis. Before the analysis with GC-MS, samples were derivatized by N,O-bis (trimethylsilyl) trifluoroacetamide (BSTFA) plus 1% trimethylchlorosilane (TMCS) at 808C for 40 min. Satisfactory recoveries ranging from 64 to 112.3% were obtained by spiking ultra-purified water, raw, and treated municipal wastewater with the six estrogens at 50, 100, and 50 ng/L, respectively. The method was successfully applied to wastewater samples from one WWTP, which suggested that E1 was the dominant natural estrogens in effluent and E3-3S was one of the conjugates possibly occurring in the effluent.

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Some new aspects of 17α-estradiol metabolism in man

Cited by 37 publications

References 22 publications

Male lifespan extension with 17‐α estradiol is linked to a sex‐specific metabolomic response modulated by gonadal hormones in mice

Male lifespan extension with 17‐α estradiol is linked to a sex‐specific metabolomic response modulated by gonadal hormones in mice

The Configuration of the 17-Hydroxy Group Variably Influences the Glucuronidation of β-Estradiol and Epiestradiol by Human UDP-Glucuronosyltransferases

Simultaneous Analysis of Natural Free Estrogens and Their Sulfate Conjugates in Wastewater

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