Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1985 Apr;75(4):1335–1338. doi: 10.1172/JCI111834

Origin of urinary nonconjugated 19-nor-deoxycorticosterone and metabolism of infused radiolabeled 19-nor-deoxycorticosterone in men and women.

M L Casey, A Guerami, L Milewich, C E Gomez-Sanchez, P C MacDonald
PMCID: PMC425463  PMID: 3988939

Abstract

It is known that 19-nor-deoxycorticosterone (19-nor-DOC) is a potent mineralocorticosteroid that is present in urine of rats and humans in a free, i.e., nonconjugated, form. In some forms of hypertension in rats, the levels of free 19-nor-DOC in urine are increased compared with those in urine of normotensive animals. Yet, despite the potential importance of this mineralocorticosteroid in the pathogenesis of certain forms of hypertension, little is known of its site of origin or metabolism. In the present investigation, we evaluated the metabolism of intravenously infused [3H]19-nor-DOC and the possibility that 19-nor-DOC was formed from plasma DOC. We found that the metabolism of [3H]19-nor-DOC infused intravenously in men and women was similar to that of DOC with important exceptions. The majority of the radiolabeled urinary metabolites of intravenously infused [3H]19-nor-DOC were excreted in urine as glucuronosides. Little radioactivity, infused as [3H]19-nor-DOC, was recovered in urine as nonconjugated or sulfoconjugated steroids. There was no free radiolabeled 19-nor-DOC in urine after the simultaneous infusion of [3H]19-nor-DOC and [14C]DOC. A major metabolite of [3H]19-nor-DOC in urine was 19-nor-DOC-21-glucuronoside, whereas little or no intravenously infused radiolabeled DOC was excreted as radiolabeled DOC-glucuronoside. We also found that intravenously infused [14C]DOC was not converted to urinary [14C]19-nor-DOC (glucuronoside) and that other tritium-labeled metabolites of infused [3H]19-nor-DOC contained no carbon-14. The production rate of 19-nor-DOC, computed from the specific activity of urinary 19-nor-DOC (glucuronoside), in one normal man was 16 micrograms/d and in the two women of this study, it was 10 micrograms/d. These findings are supportive of the proposition that free urinary 19-nor-DOC is not formed from plasma DOC; it may be formed in kidney from a precursor other than DOC or it may be formed nonenzymatically in kidney or urine from a precursor such as 19-oic-DOC.

Full text

PDF
1335

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. AXELRAD B. J., CATES J. E., JOHNSON B. B., LUETSCHER J. A., Jr Bioassay of mineralocorticoids: relationship of structure to physiological activity. Endocrinology. 1954 Nov;55(5):568–574. doi: 10.1210/endo-55-5-568. [DOI] [PubMed] [Google Scholar]
  2. BURSTEIN S., LIEBERMAN S. Hydrolysis of ketosteroid hydrogen sulfates by solvolysis procedures. J Biol Chem. 1958 Aug;233(2):331–335. [PubMed] [Google Scholar]
  3. Bokkenheuser V. D., Winter J., Dehazya P., Kelly W. G. Isolation and characterization of human fecal bacteria capable of 21-dehydroxylating corticoids. Appl Environ Microbiol. 1977 Nov;34(5):571–575. doi: 10.1128/aem.34.5.571-575.1977. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Casey M. L., Guerami A., Winkel C. A., MacDonald P. C. The origin of and metabolic fate of deoxycorticosterone and deoxycorticosterone sulfate in pregnant women and their fetuses. J Steroid Biochem. 1984 Jan;20(1):237–243. doi: 10.1016/0022-4731(84)90210-3. [DOI] [PubMed] [Google Scholar]
  5. Casey M. L., MacDonald P. C. Extraadrenal formation of a mineralocorticosteroid: deoxycorticosterone and deoxycorticosterone sulfate biosynthesis and metabolism. Endocr Rev. 1982 Fall;3(4):396–403. doi: 10.1210/edrv-3-4-396. [DOI] [PubMed] [Google Scholar]
  6. Casey M. L., MacDonald P. C. Formation of deoxycorticosterone from progesterone in extraadrenal tissues: demonstration of steroid 21-hydroxylase activity in human aorta. J Clin Endocrinol Metab. 1982 Oct;55(4):804–806. doi: 10.1210/jcem-55-4-804. [DOI] [PubMed] [Google Scholar]
  7. Casey M. L., MacDonald P. C. Metabolism of deoxycorticosterone and deoxycorticosterone sulfate in men and women. J Clin Invest. 1982 Aug;70(2):312–319. doi: 10.1172/JCI110619. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Casey M. L., Winkel C. A., MacDonald P. C. Conversion of progesterone to deoxycorticosterone in the human fetus: steroid 21-hydroxylase activity in fetal tissues. J Steroid Biochem. 1983 Apr;18(4):449–452. doi: 10.1016/0022-4731(83)90064-x. [DOI] [PubMed] [Google Scholar]
  9. Dale S. L., Holbrook M. M., Komanicky P., Melby J. C. Urinary 19-nor-deoxycorticosterone excretion in the spontaneously hypertensive rat. Endocrinology. 1982 Jun;110(6):1989–1993. doi: 10.1210/endo-110-6-1989. [DOI] [PubMed] [Google Scholar]
  10. Dale S. L., Holbrook M. M., Melby J. C. 19-Nor-deoxycorticosterone in the neutral fraction of human urine. Steroids. 1981 Jan;37(1):103–109. doi: 10.1016/0039-128x(81)90012-x. [DOI] [PubMed] [Google Scholar]
  11. Dale S. L., Holbrook M. M., Melby J. C. Identification of 19-hydroxydeoxycorticosterone in regenerating rat adrenal incubations. Steroids. 1980 Nov;36(5):601–609. doi: 10.1016/0039-128x(80)90082-3. [DOI] [PubMed] [Google Scholar]
  12. Funder J. W., Mercer J., Ingram B., Feldman D., Wynne K., Adam W. R. 19-Nor deoxycorticosterone (19-nor DOC): mineralocorticoid receptor affinity higher than aldosterone, electrolyte activity lower. Endocrinology. 1978 Oct;103(4):1514–1517. doi: 10.1210/endo-103-4-1514. [DOI] [PubMed] [Google Scholar]
  13. Gomez-Sanchez C. E., Gomez-Sanchez E. P., Shackleton C. H., Milewich L. Identification of 19-hydroxydeoxycorticosterone, 19-oxo-deoxycorticosterone, and 19-oic-deoxycorticosterone as products of deoxycorticosterone metabolism by rat adrenals. Endocrinology. 1982 Feb;110(2):384–389. doi: 10.1210/endo-110-2-384. [DOI] [PubMed] [Google Scholar]
  14. Gomez-Sanchez C. E., Gomez-Sanchez E. P., Upcavage R. J. Radioimmunoassay for urinary free 19-nor-deoxycorticosterone: effects of adrenocorticotropin and sodium depletion. Endocrinology. 1983 Jun;112(6):2046–2049. doi: 10.1210/endo-112-6-2046. [DOI] [PubMed] [Google Scholar]
  15. Gomez-Sanchez C. E., Holland O. B., Murry B. A., Lloyd H. A., Milewich L. 19-nor-deoxycorticosterone: a potent mineralcocorticoid isolated from the urine of rats with regenerating adrenals. Endocrinology. 1979 Sep;105(3):708–715. doi: 10.1210/endo-105-3-708. [DOI] [PubMed] [Google Scholar]
  16. Griffing G. T., Dale S. L., Holbrook M. M., Melby J. C. 19-nor-deoxycorticosterone excretion in healthy and hypertensive subjects. Trans Assoc Am Physicians. 1981;94:301–309. [PubMed] [Google Scholar]
  17. Griffing G. T., Dale S. L., Holbrook M. M., Melby J. C. 19-nor-deoxycorticosterone excretion in primary aldosteronism and low renin hypertension. J Clin Endocrinol Metab. 1983 Feb;56(2):218–221. doi: 10.1210/jcem-56-2-218. [DOI] [PubMed] [Google Scholar]
  18. Griffing G. T., Dale S. L., Holbrook M. M., Melby J. C. The regulation of urinary free 19-nor-deoxycorticosterone and its relation to systemic arterial blood pressure in normotensive and hypertensive subjects. J Clin Endocrinol Metab. 1983 Jan;56(1):99–103. doi: 10.1210/jcem-56-1-99. [DOI] [PubMed] [Google Scholar]
  19. Griffing G. T., Wilson T. E., Holbrook M. M., Dale S. L., Jackson T. K., Ullrich I., Melby J. C. Plasma and urinary 19-nor-deoxycorticosterone in 17 alpha-hydroxylase deficiency syndrome. J Clin Endocrinol Metab. 1984 Nov;59(5):1011–1015. doi: 10.1210/jcem-59-5-1011. [DOI] [PubMed] [Google Scholar]
  20. Griffing G. T., Wilson T. E., Melby J. C. Transitory increment in urinary free 19-nor-deoxycorticosterone after diuretic-induced renin stimulation. J Clin Endocrinol Metab. 1984 Nov;59(5):931–935. doi: 10.1210/jcem-59-5-931. [DOI] [PubMed] [Google Scholar]
  21. Guerami A., Casey M. L., MacDonald P. C. Metabolic clearance rate of plasma deoxycorticosterone sulfate in men and women. J Steroid Biochem. 1983 Aug;19(2):1173–1177. doi: 10.1016/0022-4731(83)90413-2. [DOI] [PubMed] [Google Scholar]
  22. Hall C. E., Gomez-Sanchez C. E., Holland O. B., Nasseth D. Influence of 19-nor-deoxycorticosterone on blood pressure, saline consumption, and serum electrolytes, corticosterone, and renin activity. Endocrinology. 1979 Sep;105(3):600–604. doi: 10.1210/endo-105-3-600. [DOI] [PubMed] [Google Scholar]
  23. KAGAWA C. M., VAN ARMAN C. G. Sodium retaining activity of 19-nor-steroids in adrenalectomized rats. Proc Soc Exp Biol Med. 1957 Mar;94(3):444–447. doi: 10.3181/00379727-94-22972. [DOI] [PubMed] [Google Scholar]
  24. MacDonald P. C., Cutrer S., MacDonald S. C., Casey M. L., Parker C. R., Jr Regulation of extraadrenal steroid 21-hydroxylase activity. Increased conversion of plasma progesterone to deoxycorticosterone during estrogen treatment of women pregnant with a dead fetus. J Clin Invest. 1982 Feb;69(2):469–478. doi: 10.1172/JCI110471. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Mathis J. M., Johnston J. D., MacDonald P. C., Casey M. L. Steroid 21-sulfatase activity in human placenta. J Steroid Biochem. 1983 May;18(5):575–579. doi: 10.1016/0022-4731(83)90133-4. [DOI] [PubMed] [Google Scholar]
  26. Melby J. C., Dale S. L., Holbrook M., Griffing G. T. 19-Nor-corticosteroids in experimental and human hypertension. Clin Exp Hypertens A. 1982;4(9-10):1851–1867. doi: 10.3109/10641968209061645. [DOI] [PubMed] [Google Scholar]
  27. Parker C. R., Jr, Winkel C. A., Rush A. J., Jr, Porter J. C., MacDonald P. C. Plasma concentrations of 11-deoxycorticosterone in women during the menstrual cycle. Obstet Gynecol. 1981 Jul;58(1):26–30. [PubMed] [Google Scholar]
  28. Shackleton C. H. Evidence against significant 19-nor-deoxycorticosterone production in patients with 17 alpha-hydroxylase deficiency. Clin Exp Hypertens A. 1982;4(9-10):1529–1539. doi: 10.3109/10641968209061623. [DOI] [PubMed] [Google Scholar]
  29. Winkel C. A., Casey M. L., Simpson E. R., MacDonald P. C. Deoxycorticosterone biosynthesis from progesterone in kidney tissue of the human fetus. J Clin Endocrinol Metab. 1981 Jul;53(1):10–15. doi: 10.1210/jcem-53-1-10. [DOI] [PubMed] [Google Scholar]
  30. Winkel C. A., Milewich L., Parker C. R., Jr, Gant N. F., Simpson E. R., MacDonald P. C. Conversion of plasma progesterone to deoxycorticosterone in men, nonpregnant and pregnant women, and adrenalectomized subjects. J Clin Invest. 1980 Oct;66(4):803–812. doi: 10.1172/JCI109918. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Winkel C. A., Parker C. R., Jr, Simpson E. R., MacDonald P. C. Production rate of deoxycorticosterone in women during the follicular and luteal phases of the ovarian cycle: the role of extraadrenal 21-hydroxylation of circulating progesterone in deoxycorticosterone production. J Clin Endocrinol Metab. 1980 Dec;51(6):1354–1358. doi: 10.1210/jcem-51-6-1354. [DOI] [PubMed] [Google Scholar]
  32. Winkel C. A., Simpson E. R., Milewich L., MacDonald P. C. Deoxycorticosterone biosynthesis in human kidney: potential for formation of a potent mineralocorticosteroid in its site of action. Proc Natl Acad Sci U S A. 1980 Dec;77(12):7069–7073. doi: 10.1073/pnas.77.12.7069. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Winter J., Bokkenheuser V. D. 21-dehydroxylation of corticoids by anaerobic bacteria isolated from human fecal flora. J Steroid Biochem. 1978 May;9(5):379–384. doi: 10.1016/0022-4731(78)90604-0. [DOI] [PubMed] [Google Scholar]
  34. Wynne K. N., Mercer J., Stockigt J. R., Funder J. W. 19-nor analogs of adrenal steroids: mineralocorticoid and glucocorticoid receptor activity. Endocrinology. 1980 Nov;107(5):1278–1280. doi: 10.1210/endo-107-5-1278. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES