The hydroxylation (and indirect oxidation) of 17B-estradiol into 4-hydroxyestrone.
The chemical structure of 4-OHE1 is ahydroxylated and oxidized form of17β-estradiol (17β-E2). Specifically the 4th position of theestrogen ring in17β-E2 is hydroxylated and the 17th position of the . Structural comparisons between 4-OHE1 and17β-E2 show a congruentsteroid backbone, but the additionalhydroxyl group in 4-OHE1 changes its biochemical properties. 4-OHE1 exhibits enhancedcarcinogenic activities within the human body as compared to17β-E2.[15][16][17]
Biochemical Studies Related to 4-OHE1's Role as a Carcinogen and Neuroestrogen
4-OHE1 behaves similarly to17β-E2 inelectron emission processes. A study onelectron emission of17β-E2 demonstrated that 4-OHE1, as a secondary metabolite, can emit electrons in a similar mechanism post-UV excitation.[15] Additionally, studies related to thecentral nervous system (CNS) observed that the hydroxylation process in17β-E2 also occurs in cerebral enzymes.[1]
In 2019, 4-OHE1 was detected within human urine from breast cancer patients, reinforcing its association with cancer. Moreover, 4-OHE1 has been found to conferchemotherepeutic resistance, againstdocetaxel.[16]
In 2020, studies comparing17β-E2 and hydroxy esterone revealed that 4-OHE1 contributes to thecytoplasmictranslocation ofp53, a key tumor supressor protein, contributing to its role in cellular responses fromstress and damage.[1]
Earlier research has indicated that natural estrogens can help protect the brain from oxidative harm. This current study aims to explore how different estrogen metabolites produced by the body can guard against neurotoxicity caused by oxidation, both in lab settings and in live subjects. When testing 25 endogenous estrogen metabolites using mouse hippocampal neuron cells, researchers found that 4-hydroxyestrone—a metabolite of estrone with minimal estrogen-like activity—was surprisingly effective at shielding neurons from oxidative stress. It even outperformed 17β-estradiol! Likewise, when looking at rats exposed to kanic acid-induced damage in their hippocampus, 4-hydroxyestrone showed a stronger protective effect compared to 17β-estradiol as well. The way it works is linked to an increase in p53 movement within cells due to SIRT1-mediated deacetylation of p53. Further examination of brain enzymes revealed that converting estrogens into their hydroxylated forms is a key metabolic route within the central nervous system. All these findings point towards 4-hydroxyestrone being a powerful neuroestrogen capable of providing significant protection against neuronal oxidative injury.[18]
Hydroxyestrone (4-OHE1), a well-known cancer-causing metabolite that comes from 17β-estradiol (17β-E2), was picked as the subject for these studies. The goal was to dig deeper into how it kicks off cancer development. It turns out that when 4-OHE1 is energized in its singlet state using monochromatic UV light at a wavelength of 254 nm within polar environments like a water-ethanol mix (40:60 vol%), it can actually release electrons (e aq -).[19]
^Bhavnani BR, Nisker JA, Martin J, Aletebi F, Watson L, Milne JK (2000). "Comparison of pharmacokinetics of a conjugated equine estrogen preparation (premarin) and a synthetic mixture of estrogens (C.E.S.) in postmenopausal women".Journal of the Society for Gynecologic Investigation.7 (3):175–83.doi:10.1016/s1071-5576(00)00049-6.PMID10865186.
^Martucci C, Fishman J (March 1976). "Uterine estrogen receptor binding of catecholestrogens and of estetrol (1,3,5(10)-estratriene-3,15alpha,16alpha,17beta-tetrol)".Steroids.27 (3):325–333.doi:10.1016/0039-128x(76)90054-4.PMID178074.S2CID54412821.
^Martucci C, Fishman J (December 1977). "Direction of estradiol metabolism as a control of its hormonal action--uterotrophic activity of estradiol metabolites".Endocrinology.101 (6):1709–1715.doi:10.1210/endo-101-6-1709.PMID590186.
^Martucci CP, Fishman J (December 1979). "Impact of continuously administered catechol estrogens on uterine growth and luteinizing hormone secretion".Endocrinology.105 (6):1288–1292.doi:10.1210/endo-105-6-1288.PMID499073.
^Fishman J, Martucci CP (1980). "New Concepts of Estrogenic Activity: the Role of Metabolites in the Expression of Hormone Action". In Pasetto N, Paoletti R, Ambrus JL (eds.).The Menopause and Postmenopause. pp. 43–52.doi:10.1007/978-94-011-7230-1_5.ISBN978-94-011-7232-5.
^Fishman J, Martucci C (September 1980). "Biological properties of 16 alpha-hydroxyestrone: implications in estrogen physiology and pathophysiology".The Journal of Clinical Endocrinology and Metabolism.51 (3):611–615.doi:10.1210/jcem-51-3-611.PMID7190977.
