Metabolism of exogenous 4- and 2-hydroxyestradiol in the human male

https://doi.org/10.1016/0022-4731(87)90508-5Get rights and content

Abstract

The metabolic fate of the isomeric catecholestrogens 4-hydroxyestradiol (4-OHE2) and 2-hydroxyestradiol (2-OHE2) was studied to elucidate possible differences in their metabolism as an explanation for their different bioactivities. Healthy young men (n = 3 each) were infused (90 min) with 4-OHE2 (60 μg/h) or 2-OHE2 (100 μg/h). The main metabolites were determined in plasma and urine before, during and after infusion. Unconjugated and conjugated steroids, the latter after hot acid hydrolysis, were subjected to chromatography on LH-20 columns and measured by specific RIAs. During the infusion 4-OHE2 reached significant plasma concentrations whereas 2-OHE2 was so rapidly metabolised that its plasma levels remained virtually undetectable in spite of a higher infusion rate. The metabolism of 4-OHE2 was dominated by direct conjugation, that of 2-OHE2 by methyl ether formation. These findings were corroborated by the urinary excretion rates: during the infusion and the first hours afterwards, 4-OHE2 was mainly excreted as 4-OHE2 and 4-hydroxyestrone, while 2-OHE2 was predominantly excreted as 2-hydroxyestradiol 2-methyl ether and 2-hydroxyestrone 2-methyl ether.

References (21)

  • N.J. MacLusky et al.

    The catechol estrogens

    J. steroid Biochem.

    (1981)
  • R. Knuppen et al.

    Importance of A-ring substitution of estrogens for the physiology and pharmacology of reproduction

    J. steroid Biochem.

    (1986)
  • P. Ball et al.

    Radioimmunoassay of 2-hydroxyestrone and 2-methoxyestrone in human urine

    Steroids

    (1979)
  • P. Ball et al.

    Radioimmunoassay of 2-hydroxyestrone

    Steroids

    (1978)
  • P. Ball et al.

    Catecholestrogens (2- and 4-hydroxyestrogens). Chemistry, biogenesis, metabolism, occurrence and physiological significance

    Acta endocr. Copenh.

    (1980)
  • J. Fishman

    Biological action of catecholestrogens

    J. Endocr.

    (1981)
  • G. Emons et al.

    Radioimmunoassays of catecholestrogens

  • G. Emons et al.

    Biphasic modulation of pituitary sensitivity to GnRH by oestrogens: the effects of A- and D-ring substitution on LH-release in cultured pituitary cells

    Acta endocr., Copenh.

    (1984)
  • G. Emons et al.

    Effects of different substituents in the A-ring of estradiol on its potency in sensitizing pituicytes to gonadotropin releasing hormone

  • R.F. Aten et al.

    Separation of steroidal estrogens and their major unconjugated metabolites by high-performance liquid chromatography

    J. steroid Biochem.

    (1982)
There are more references available in the full text version of this article.

Cited by (38)

  • Design and synthesis of selective CYP1B1 inhibitor via dearomatization of α-naphthoflavone

    2019, Bioorganic and Medicinal Chemistry
    Citation Excerpt :

    such as breast cancer and ovarian cancer (Fig. 1). 2-Hydroxylation of E2 regulated by CYP1A1 and CYP1A2 has been recognized as a major inactivation pathway of E2, which affords 2-hydroxy-E2 (2OHE2) as a metabolite,14,17 and methylation by catechol-O-methyltransferase (COMT) affords an inactivated metabolite.18 On the other hand, CYP1B1 produces 4-hydroxy-E2 (4OHE2).19

  • Whole flaxseed diet alters estrogen metabolism to promote 2-methoxtestradiol-induced apoptosis in hen ovarian cancer

    2017, Journal of Nutritional Biochemistry
    Citation Excerpt :

    We have previously established that 15% whole flaxseed-supplemented diet increases the serum 2-hydroxyestradiol/16-hydroxyestradiol ratio, in turn suggesting a reduced risk of cancer [12]. The 2-hydroxy and 4-hydroxy metabolites are oxidized by catechol-o-methyl transferase (COMT) to methoxy-metabolites [13]. 2-hydroxyestradiol is preferentially converted to 2-methoxyestradiol [14], whereas 4-hydroxyestradiol is readily oxidized to the 3,4 quinone, a genotoxic metabolite.

  • Estrogen-induced reactive oxygen species-mediated signalings contribute to breast cancer

    2011, Biochimica et Biophysica Acta - Reviews on Cancer
    Citation Excerpt :

    Although neither 2-OH-E2 nor 2-OH-E1 is carcinogenic in vitro or in vivo [42,54,55], both 2-OH-E2 and 2-OH-E1 are capable of producing ROS and undergo metabolic redox cycling like 4-OH-E2. The lack of carcinogenicity of 2-hydroxylated estrogen metabolites in vivo may be due to their rapid inactivation by catechol-O-methyltransferase (COMT)-mediated O-methylation [55–57], rapid clearance [58], and weak estrogenic hormonal activity (compared with 4-OH-E2) [59]. It may also be due to 2-MeO-E2, the major product of COMT-mediated O-methylation of 2-OH-E2 that possesses unique anti-tumorigenic activity.

View all citing articles on Scopus

This study was presented in part at the 12th Acta Endocrinologica Congress, Stockholm, Sweden 1983 and at the 30th Symposium of the Deutsche Gesellschaft für Endokrinologie, München, F.R.G., 1986.

View full text