Chemistry:11-Deoxycortisol

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11-Deoxycortisol
Names
IUPAC name
17α,21-Dihydroxypregn-4-ene-3,20-dione
Systematic IUPAC name
(1R,3aS,3bR,9aR,9bS,11aS)-1-Hydroxy-1-(2-hydroxy-1-oxoethyl)-9a,11a-dimethyl-1,2,3,3a,3b,4,5,8,9,9a,9b,10,11,11a-tetradecahydro-7H-cyclopenta[a]phenanthren-7-one
Other names
11-Deoxycortisol; 11-Deoxycortisone; Cortoxelone; 17α,21-Dihydroxyprogesterone; 11-Desoxycortisol; 11-Deoxyhydrocortisone; 11-Desoxyhydrocortisone; 17α-Hydroxy-11-deoxycorticosterone; Reichstein's Substance S; Compound S; Cortodoxone; Cortexolone,
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
KEGG
UNII
Properties
C21H30O4
Molar mass 346.467 g·mol−1
Melting point 215 °C (419 °F; 488 K)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references
Tracking categories (test):

11-Deoxycortisol, also known as cortodoxone (INN), cortexolone[1][2][3][4] as well as 17α,21-dihydroxyprogesterone or 17α,21-dihydroxypregn-4-ene-3,20-dione,[5] is an endogenous glucocorticoid steroid hormone, and a metabolic intermediate towards cortisol. It was first described by Tadeusz Reichstein in 1938 as Substance S,[6] thus has also been referred to as Reichstein's Substance S[5] or Compound S.[7][8]

Function

Steroidogenesis, showing 11-deoxycortisol in the pathway from cholesterol to cortisol.[9]

11-Deoxycortisol acts as a glucocorticoid, though is less potent than cortisol.[10] Although 11-deoxycortisol itself has weaker glucocorticoid activity compared to cortisol, it can still bind to glucocorticoid receptors and exert certain metabolic and anti-inflammatory effects, and participates in feedback mechanisms involved in regulating the secretion of adrenocorticotropic hormone (ACTH) from the pituitary gland by inhibiting its production.

11-Deoxycortisol is synthesized from 17α-hydroxyprogesterone by 21-hydroxylase and is converted to cortisol by 11β-hydroxylase.

11-Deoxycortisol in mammals has limited biological activity and mainly acts as metabolic intermediate within the glucocorticoid pathway, leading to cortisol.[11] However, in sea lampreys, an early jawless fish species that originated over 500 million years ago, 11-deoxycortisol plays a crucial role as the primary and ultimate glucocorticoid hormone with mineralocorticoid properties; 11-deoxycortisol also takes part, by binding to specific corticosteroid receptors, in intestinal osmoregulation in sea lamprey at metamorphosis, during which they develop seawater tolerance before downstream migration.[12] Sea lampreys do not possess the 11β-hydroxylase enzyme (CYP11B1) responsible for converting 11-deoxycortisol to cortisol and 11-deoxycorticosterone to corticosterone, as observed in mammals. The absence of this enzyme in sea lampreys indicates the existence of a complex and highly specific corticosteroid signaling pathway that emerged at least 500 million years ago with the advent of early vertebrates. The lack of cortisol and corticosterone in sea lampreys suggests that the presence of the 11β-hydroxylase enzyme may have been absent during the early stages of vertebrate evolution.[13] The absence of cortisol and corticosterone in sea lampreys suggests that the 11β-hydroxylase enzyme may not have been present early in vertebrate evolution.[14]

Clinical significance

11-Deoxycortisol in mammals has limited glucocorticoid activity, but it is the direct precursor of the major mammalian glucocorticoid, cortisol.[15] As a result, the level of 11-deoxycortisol is measured to diagnose impaired cortisol synthesis, to find out the enzyme deficiency that causes impairment along the pathway to cortisol, and to differentiate adrenal disorders.[16]

In 11β-hydroxylase deficiency, 11-deoxycortisol and 11-deoxycorticosterone levels increase, and excess of 11-deoxycorticosterone leads to mineralocorticoid-based hypertension[17] (as opposed to 21-hydroxylase deficiency, in which patients have low blood pressure from a lack of mineralocorticoids). Low levels of cortisol can affect blood pressure by causing a decrease in sodium retention and volume expansion. This is because cortisol plays a role in regulating the balance of water and electrolytes in the body. When cortisol levels are low, there is less sodium reabsorption by the kidneys, leading to increased excretion of sodium through urine. This ultimately reduces blood volume and lowers blood pressure. On the other hand, high levels of cortisol can also affect blood pressure by causing an increase in sodium retention and volume expansion. Cortisol-induced hypertension is accompanied by significant sodium retention, leading to an increase in extracellular fluid volume and exchangeable sodium. This results in an increase in blood volume and subsequently increases blood pressure. The underlying mechanisms for these effects involve various factors such as suppression of the nitric oxide system, alterations in vascular responsiveness to pressor agonists like adrenaline, increased cardiac output or stroke volume due to plasma volume expansion, and potential dysregulation of glucocorticoid receptors or 11β-hydroxylase enzyme activity. It's important to note that these mechanisms may be relevant not only for cortisol-induced hypertension but also for conditions such as Cushing's syndrome (excess cortisol production), apparent mineralocorticoid excess (related to defects in 11β-hydroxylase enzymes), liquorice abuse (glycyrrhetinic acid affecting glycyerrhetinic acid receptor), chronic renal failure (prolonged half-life of cortisol due to reduced 11β-hydroxylase activity), and even essential hypertension where there may be abnormalities with 11β-hydroxylase activity or glucocorticoid receptor variations.[18][19][20] Low levels of cortisol lead to reduced vascular tone as cortisol helps maintain normal vascular tone by promoting vasoconstriction. Low levels of cortisol can lead to decreased vasoconstriction, resulting in relaxed blood vessels and lower overall blood pressure. Also, low cortisol levels lead to impaired fluid balance, as cortisol affects fluid balance by influencing sodium and water reabsorption in the kidneys. When cortisol levels are low, sodium absorption may be reduced, leading to increased excretion of sodium in the urine and subsequent lowering of blood volume and blood pressure. Additionally, low levels of cortisol cause a dysregulated renin-angiotensin system, as cortisol interacts with the renin-angiotensin system, which regulates blood pressure through vasoconstriction and fluid balance. Low cortisol levels can disrupt this system, leading to altered angiotensin production, reduced aldosterone secretion, and subsequently lower blood pressure. Conversely, high levels of cortisol lead to increased vascular tone, enhanced sodium retention, and increased sympathetic activity. Stress-induced release of high-level glucocorticoids such as cortisol activates the sympathetic nervous system (SNS). The SNS controls heart rate, cardiac output, and vasomotor tone, causing constriction, and thereby increasing peripheral arterial resistance, resulting in an increase in blood pressure.[21] In 11β-hydroxylase deficiency, 11-deoxycortisol can also be converted to androstenedione in a pathway that could explain the increase in androstenedione levels this condition.[22]

In 21-hydroxylase deficiency, 11-deoxycortisol levels are low.[23]

History

In 1934, biochemist Tadeus Reichstein, working in Switzerland , began research on extracts from animal adrenal glands in order to isolate physiologically active compounds.[24] He was publishing results of his findings along the way. By 1944, he already isolated and elucidated the chemical structure of 29 pure substances.[25] He was assigning names that consisted of the word "Substance" and a letter from the Latin alphabet to the newly found substances. In 1938, he published an article about "Substance R" and "Substance S" describing their chemical structures and properties.[6] The Substance S since about 1955 became known as 11-Deoxycortisol.[26]

In the 1930s and 1940s clinicians were discovering many uses for the newly discovered hormones, however, only minute quantities could be extracted from animal organs. Chemists were looking for the production of these hormones on a larger industrial scale.

In 1949, American research chemist Percy Lavon Julian, in looking for ways to produce cortisone, announced the synthesis of the Compound S, from the cheap and readily available pregnenolone (synthesized from the soybean oil sterol stigmasterol).[27][28]

On 5 April 1952, biochemist Durey Peterson and microbiologist Herbert Murray at Upjohn, published the first report of a breakthrough fermentation process for the microbial 11α-oxygenation of steroids (e.g. progesterone) in a single step by common molds of the order Mucorales.[29] 11α-oxygenation of Compound S produces 11α-hydrocortisone, which can be chemically oxidized to cortisone, or converted by further chemical steps to 11β-hydrocortisone (cortisol).

See also

References

  1. ↑ "The dual androgen receptor and glucocorticoid receptor antagonist CB-03-10 as a potential treatment for tumors that have acquired GR-mediated resistance to AR blockade". Molecular Cancer Therapeutics 19 (11): 2256–2266. August 2020. doi:10.1158/1535-7163.MCT-19-1137. PMID 32847976. 
  2. ↑ "[A study of steroid hydroxylation activity of Curvularia lunata mycelium]" (in ru). Prikladnaia Biokhimiia I Mikrobiologiia 43 (6): 695–700. 2007. PMID 18173113. 
  3. ↑ "Biotransformation of cortexolone to hydrocortisone by molds using a rapid color development assay". Prikladnaia Biokhimiia I Mikrobiologiia 42 (5): 547–51. 2006. PMID 17066954. 
  4. ↑ "Concurrent corticosteroid and phenanthrene transformation by filamentous fungus Cunninghamella elegans". The Journal of Steroid Biochemistry and Molecular Biology 85 (1): 63–9. May 2003. doi:10.1016/s0960-0760(03)00136-5. PMID 12798358. 
  5. ↑ 5.0 5.1 R.A. Hill; H.L.J. Makin; D.N. Kirk; G.M. Murphy (23 May 1991). Dictionary of Steroids. CRC Press. pp. 338–. ISBN 978-0-412-27060-4. https://books.google.com/books?id=qw5X0NK1A90C&pg=PA338. 
  6. ↑ 6.0 6.1 "Über Bestandteile der Nebennierenrinde. 21. Mitteilung. Die Konstitution der Substanzen R und S". Helvetica Chimica Acta 21: 1490–1497. 1938. doi:10.1002/hlca.193802101183. https://onlinelibrary.wiley.com/doi/10.1002/hlca.193802101183. 
  7. ↑ "Determination of 11-deoxycortisol (Reichstein's compound S) in human plasma by clinical isotope dilution mass spectrometry using benchtop gas chromatography-mass selective detection". Steroids 67 (10): 851–7. September 2002. doi:10.1016/s0039-128x(02)00052-1. PMID 12231120. 
  8. ↑ "Combined stimulation of adrenocorticotropin and compound-S by single dose metyrapone test as an outpatient procedure to assess hypothalamic-pituitary-adrenal function". The Journal of Clinical Endocrinology and Metabolism 87 (12): 5470–5. December 2002. doi:10.1210/jc.2001-011959. PMID 12466339. 
  9. ↑ Häggström, Mikael; Richfield, David (2014). "Diagram of the pathways of human steroidogenesis". WikiJournal of Medicine 1 (1). doi:10.15347/wjm/2014.005. ISSN 2002-4436. 
  10. ↑ "Glucocorticoid Activity of Adrenal Steroid Precursors in Untreated Patients With Congenital Adrenal Hyperplasia". The Journal of Clinical Endocrinology and Metabolism 104 (11): 5065–5072. November 2019. doi:10.1210/jc.2019-00547. PMID 31090904. 
  11. ↑ "Congenital Adrenal Hyperplasia Caused by 11Beta-Hydroxylase Deficiency". https://www.merckmanuals.com/professional/pediatrics/endocrine-disorders-in-children/congenital-adrenal-hyperplasia-caused-by-11beta-hydroxylase-deficiency. 
  12. ↑ "Corticosteroid control of Na+/K+-ATPase in the intestine of the sea lamprey (Petromyzon marinus)". General and Comparative Endocrinology 307: 113756. March 2021. doi:10.1016/j.ygcen.2021.113756. PMID 33741310. 
  13. ↑ "11-Deoxycortisol controls hydromineral balance in the most basal osmoregulating vertebrate, sea lamprey (Petromyzon marinus)". Scientific Reports 10 (1): 12148. July 2020. doi:10.1038/s41598-020-69061-4. PMID 32699304. Bibcode: 2020NatSR..1012148S. 
  14. ↑ "11-deoxycortisol is a corticosteroid hormone in the lamprey". Proceedings of the National Academy of Sciences of the United States of America 107 (31): 13942–7. August 2010. doi:10.1073/pnas.0914026107. PMID 20643930. Bibcode: 2010PNAS..10713942C. 
  15. ↑ "Purification and functional characterization of human 11beta hydroxylase expressed in Escherichia coli". The FEBS Journal 275 (4): 799–810. February 2008. doi:10.1111/j.1742-4658.2008.06253.x. PMID 18215163. 
  16. ↑ "Serum steroid levels can help differentiate adrenal disorders". https://www.healio.com/news/endocrinology/20190430/serum-steroid-levels-can-help-differentiate-adrenal-disorders. 
  17. ↑ "Mineralocorticoid hypertension". Indian Journal of Endocrinology and Metabolism 15 (Suppl 4): S298-312. October 2011. doi:10.4103/2230-8210.86972. PMID 22145132. 
  18. ↑ "Cortisol and hypertension". Clin Exp Pharmacol Physiol Suppl 25: S51–6. November 1998. doi:10.1111/j.1440-1681.1998.tb02301.x. PMID 9809193. 
  19. ↑ "Cortisol, 11beta-hydroxysteroid dehydrogenases, and hypertension". Semin Vasc Med 4 (2): 121–8. May 2004. doi:10.1055/s-2004-835369. PMID 15478032. 
  20. ↑ "Cortisol, hypertension and obesity: the role of 11 beta-hydroxysteroid dehydrogenase". J R Coll Physicians Lond 32 (2): 154–9. 1998. PMID 9597634. 
  21. ↑ "Renin, Aldosterone, and Cortisol in Pregnancy-Induced Hypertension". Exp Clin Endocrinol Diabetes 131 (4): 222–227. April 2023. doi:10.1055/a-2025-0510. PMID 36807213. 
  22. ↑ "Evidence for a new biologic pathway of androstenedione synthesis from 11-deoxycortisol". Steroids 56 (1): 33–6. January 1991. doi:10.1016/0039-128X(91)90112-9. PMID 2028480. 
  23. ↑ Essential Endocrinology: A Primer for Nonspecialists. Springer Science & Business Media. 2013. p. 263. ISBN 9781489916921. 
  24. ↑ "Chemistry of the Adrenal Cortex Hormones". https://www.nobelprize.org/prizes/medicine/1950/reichstein/lecture/. 
  25. ↑ "Tadeusz Reichstein (1897-1996): a cofounder of modern steroid treatment in dermatology". Clinics in Dermatology 30 (2): 243–7. 2012. doi:10.1016/j.clindermatol.2011.09.003. PMID 22435119. 
  26. ↑ "Metabolism of 11-deoxycortisol in vitro". The Journal of Biological Chemistry 215 (2): 713–22. 1 August 1955. doi:10.1016/S0021-9258(18)65996-4. PMID 13242571. https://www.jbc.org/content/215/2/713.long. 
  27. ↑ "Science gets synthetic key to rare drug; discovery is made in Chicago". Chicago Tribune: p. 1. 30 September 1949. https://pqasb.pqarchiver.com/chicagotribune/access/494372192.html?dids=494372192:494372192&FMT=ABS&FMTS=ABS:AI. "Dr. Julian's new method for synthesizing the anti-arthritis compound, cortisone, is less costly than present methods, because it eliminates the need for utilizing osmium tetroxide, a rare and expensive chemical, the Glidden company declared....But whether has Dr. Julian has also synthesized cortisone from soybeans neither he nor the Glidden company would reveal." 
  28. ↑ "News of the week: New cortisone synthesis". Chemical & Engineering News 27 (41): 2936–2942. 10 October 1949. doi:10.1021/cen-v027n041.p2936. "Quote: A new synthesis of cortisone, eliminating the need for expensive osmium tetroxide, and the synthesis of three other compounds related to cortisone, which may possible be useful in the treatment of arthritis, have been announced by Percy L. Julian, director of research of the soya products division of the Glidden Co., Chicago. No statement was made as to further details of the new synthesis, but it was revealed that soybean products were not involved...all three [other compounds] were made from soybean sterols.". 
  29. ↑ Peterson DH; Murray, HC (1952). "Microbiological oxygenation of steroids at carbon 11". J Am Chem Soc 74 (7): 1871–2. doi:10.1021/ja01127a531. 



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