CoChat
Sign Up
Cited by 71Adrenal Hormones and DisordersEstrogen and related hormone effectsHormonal Regulation and Hypertension

The DOI matches its Crossref record; 8 of the 8 references it cites were found in a registry or an index.

Medroxyprogesterone Acetate and Dexamethasone Are Competitive Inhibitors of Different Human Steroidogenic Enzymes1

Lee, Tim C., Miller, Walter L., Auchus, Richard J.·1999·The Journal of Clinical Endocrinology & Metabolism
DOI 10.1210/jcem.84.6.5646
Open this paper in CoChat — free account

Abstract

Medroxyprogesterone acetate (MPA), a widely used progestin, can suppress the hypothalamic-pituitary-gonadal axis but can also directly inhibit gonadal steroidogenesis; the success of MPA as a treatment for gonadotropin-independent sexual precocity derives from its direct action on steroidogenic tissues. Dexamethasone, a widely used glucocorticoid, can suppress the hypothalamic-pituitary-adrenal axis, but its potential effect directly on the adrenal is unclear. Previous reports suggested that these two drugs may act on the initial steps in the rodent steroidogenic pathway; therefore, we investigated their abilities to inhibit the first three human enzymes in steroidogenesis: the cholesterol side-chain cleavage enzyme (P450scc), the 17α-hydroxylase/17,20-lyase (P450c17), and type II 3β-hydroxysteroid dehydrogenase/isomerase (3βHSDII). We found no effect of either drug on P450scc in intact human choriocarcinoma JEG-3 cells. Using microsomes from yeast expressing human P450c17 or microsomes from human adrenals, we found that dexamethasone inhibited P450c17 with a Ki of 87 μmol/L, which is about 1000 times higher than typical therapeutic concentrations, but that MPA has no detectable action on P450c17. Using microsomes from yeast expressing human 3βHSDII, we found that this enzyme has indistinguishable apparent Km values of 5.2–5.5 μmol/L and similar maximum velocities of 0.34–0.56 pmol steroid/min·μg microsomal protein for the three principal endogenous substrates, pregnenolone, 17-hydroxypregnenolone, and dehydroepiandrosterone. In this system, MPA inhibited 3βHSDII with a Ki of 3.0 μmol/L, which is near concentrations achieved by high therapeutic doses of 5–20 mg MPA/kg·day. These data establish the mechanism of action of MPA as an inhibitor of human steroidogenesis, and are in contrast with the results of earlier studies indicating that MPA inhibited both P450c17 and 3βHSD in rat Leydig cells. These studies establish the“ humanized yeast” system as a model for studying the actions of drugs on human steroidogenic enzymes and suggest that 3βHSDII may be an appropriate target for pharmacological interventions in human disorders characterized by androgen excess or sex steroid dependency.

Overview

Integrity signals

Registry

Crossref · 10.1210/jcem.84.6.5646

Cites

8 of 8 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Verification

Claims the paper makes

This paper’s full text isn’t openly available, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The zona reticularis expresses relatively little 3βHSD2, and the Km of 3βHSD2 is approximately 5 M for pregnenolone and 17-hydroxypregnenolone, whereas the Km for both activities of P450c17 is approximately 1 M, so that abundant DHEA is produced.

    “The zona reticularis expresses relatively little 3␤HSD2, and the K m of 3␤HSD2 is approximately 5 M for pregnenolone and 17-hydroxypregnenolone (188), whereas the K m for both activities of P450c17 is approximately 1 M (189), so that abundant DHEA is produced.”

    From The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders (2011) · cites this paper as [188]

Citations

Cites

Flagged first, then by citations

Research works printed but not linked: 36

  1. Rosenthal, 1983, Gonadotropin-independent familial sexual precocity with premature Leydig and germinal cell maturation (“familial testotoxicosis”): effects of a potent leutenizing hormone-releasing factor agonist and medroxyprogesterone acetate therapy in four cases., J Clin Endocrinol Metab, 57, 571, 10.1210/jcem-57-3-571 · DOI
  2. Richards, 1977, Sexual precocity associated with functional follicular cysts, prepubertal gonadotropins, and LRF response and fluctuating estrogen levels., Pediatr Res, 11, 431, 10.1203/00006450-197704000-00371 · DOI
  3. Gallagher, 1987, High dose vs. low dose medroxyprogesterone acetate: a randomized trial in advanced breast cancer., Eur J Cancer Clin Oncol, 23, 1895, 10.1016/0277-5379(87)90056-3 · DOI
  4. Nishimura, 1997, Predictive value of serum medroxyprogesterone acetate concentration for response in advanced or recurrent breast cancer., Eur J Cancer, 33, 1407, 10.1016/S0959-8049(97)00125-1 · DOI
  5. Veelen, 1984, Adrenal suppression by oral high-dose medroxyprogesterone acetate in breast cancer patients., Cancer Chemother Pharmacol, 12, 83, 10.1007/BF00254594 · DOI
  6. Veelen, 1985, Mechanism of adrenal suppression by high-dose medroxyprogesterone acetate in breast cancer patients., Cancer Chemother Pharmacol, 15, 167, 10.1007/BF00257530 · DOI
  7. 1998, Prenatal treatment of congenital adrenal hyperplasia—a promising experimental therapy of unproven safety., Trends Endocrinol Metab, 9, 290, 10.1016/S1043-2760(98)00068-X · DOI
  8. Brentano, 1990, Tissue-specific, cAMP-induced, and phorbol ester repressed expression from the human P450c17 promoter in mouse cells., Mol Endocrinol, 4, 1972, 10.1210/mend-4-12-1972 · DOI
  9. Barbieri, 1980, Direct effects of medroxyprogesterone acetate (MPA) and magestrol acetate (MGA) on rat testicular steroidogenesis., Acta Endocrinol (Copenh), 94, 419, 10.1530/acta.0.0940419 · DOI
  10. Auchus, 1998, Cytochrome b5 augments the 17,20 lyase activity of human P450c17 without direct electron transfer., J Biol Chem, 273, 3158, 10.1074/jbc.273.6.3158 · DOI · Paper page
  11. Labrie, 1997, The key role of 17β-hydroxysteroid dehydrogenases in sex steroid biology., Steroids, 62, 148, 10.1016/S0039-128X(96)00174-2 · DOI · Paper page
  12. Payne, 1997, The multiple murine 3β-hydroxysteroid dehydrogenase isoforms: structure, function, and tissue- and developmentally specific expression., Steroids, 62, 169, 10.1016/S0039-128X(96)00177-8 · DOI
  13. Simard, 1993, Molecular basis of congenital adrenal hyperplasia due to 3β-hydroxysteroid dehydrogenase deficiency., Mol Endocrinol, 7, 716
  14. Tomlinson, 1997, In vitro metabolism of dexamethasone (DEX) in human liver and kidney: the involvement of CYP3A4 and CYP17 (17,20-lyase) and molecular modeling studies., Biochem Pharmacol, 54, 605, 10.1016/S0006-2952(97)00166-4 · DOI
  15. Rhéaume, 1991, Structure and expression of a new complementary DNA encoding the almost exclusive 3β-hydroxysteroid dehydrogenase/Δ5-Δ4-isomerase in human adrenals and gonads., Mol Endocrinol, 5, 1147, 10.1210/mend-5-8-1147 · DOI · Paper page
  16. Pompon, 1996, Yeast expression of animal and plant P450s in optimized redox environments., Methods Enzymol, 272, 51, 10.1016/S0076-6879(96)72008-6 · DOI
  17. Gietz, 1992, Improved method for high efficiency transformation of intact yeast cells., Nucleic Acids Res, 20, 1425, 10.1093/nar/20.6.1425 · DOI
  18. Zhang, 1995, Serine phosphorylation of human P450c17 increases 17,20 lyase activity: implications for adrenarche and for the polycystic ovary syndrome., Proc Natl Acad Sci USA, 92, 10619, 10.1073/pnas.92.23.10619 · DOI · Paper page
  19. Lin, 1993, Steroid 17α-hydroxylase and 17,20 lyase activities of P450c17: contributions of serine106 and P450 reductase., Endocrinology, 132, 2498, 10.1210/endo.132.6.8504753 · DOI
  20. Auchus, 1989, Preparation of 14,15 secoestra-1,3,5(10)-trien-15-ynes, inhibitors of estradiol dehydrogenase., Steroids, 53, 77, 10.1016/0039-128X(89)90147-5 · DOI
  21. Auchus, 1998, The regulation of human P450c17 activity: relationship to premature adrenarche and the polycystic ovary syndrome., Trends Endocrinol Metab, 9, 47, 10.1016/S1043-2760(98)00016-2 · DOI
  22. Duport, 1998, Self-sufficient biosynthesis of pregnenolone and progesterone in engineered yeast., Nat Biotechnol, 16, 186, 10.1038/nbt0298-186 · DOI
  23. Black, 1993, Regulation of proteins of the cholesterol side-chain cleavage system in Y-1 and JEG-3 cells., Endocrinology, 132, 539, 10.1210/endo.132.2.8425475 · DOI
  24. 1997, Congenital lipoid adrenal hyperplasia: the human gene knockout of the steroidogenic acute regulatory protein., J Mol Endocrinol, 17, 227
  25. Picado-Leonard, 1987, Cloning and sequence of the human gene encoding P450c17 (steroid 17α-hydroxylase/17,20 lyase): similarity to the gene for P450c21., DNA, 6, 439, 10.1089/dna.1987.6.439 · DOI · Paper page
  26. Chung, 1987, Cytochrome P450c17 (steroid 17α-hydroxylase/17,20 lyase): cloning of human adrenal and testis cDNAs indicates the same gene is expressed in both tissues., Proc Natl Acad Sci USA, 84, 407, 10.1073/pnas.84.2.407 · DOI · Paper page
  27. Brodie, 1998, Aroomatase inihibitors in advanced breast cancer: mechanism of action and clinical implications., J Sterioid Biochem Mol Biol, 66, 1, 10.1016/S0960-0760(98)00022-3 · DOI
  28. 1995, Endocrine therapy of prostate cancer: optimal form and timing., J Clin Endocrinol Metab, 80, 1066, 10.1210/jcem.80.4.7714068 · DOI
  29. Auchus, 1994, Treatment of post-orchiectomy gynecomastia with testolactone., Endocrinologist, 4, 429, 10.1097/00019616-199411000-00005 · DOI
  30. Laue, 1996, A preliminary study of flutamide, testolactone, and reduced hydrocortisone dose in the treatment of congenital adrenal hyperplasia., J Clin Endocrinol Metab, 81, 3535
  31. McConnell, 1998, The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia., N Engl J Med, 338, 557, 10.1056/NEJM199802263380901 · DOI · Paper page
  32. Wingfield, 1993, Endometriosis: medical therapy., Balliere Clin Obstet Gynecol, 7, 813, 10.1016/S0950-3552(05)80465-1 · DOI
  33. Luu-The, 1989, Full length cDNA structure and deduced amino acid sequence of human 3β-hydroxy-5-ene steroid dehydrogenase., Mol Endocrinol, 3, 1310, 10.1210/mend-3-8-1310 · DOI
  34. Thomas, 1989, Human placental 3β-hydroxy-5-ene-steroid dehydrogenase and steroid 5→4-ene-isomerase: purification from mitochondria and kinetic profiles, biophysical characterization of the purified mitochondrial and microsomal enzymes., Steroid Biochem, 33, 209, 10.1016/0022-4731(89)90296-3 · DOI · Paper page
  35. 1994, Neurosteroids: biochemistry, modes of action, and clinical relevance., J Clin Endocrinol Metab, 78, 1003
  36. Katagiri, 1995, The role of cytochrome b5 in the biosynthesis of androgens by human P450c17., Arch Biochem Biophys, 317, 343, 10.1006/abbi.1995.1173 · DOI · Paper page

Cited by

Sorted by citations

Metadata

Authors
Lee, T. C., Miller, W. L., & Auchus, R. J.
Affiliations
  • Departments of Pediatrics (T.C.L., W.L.M., R.J.A.) San Francisco, California 94143-0978
  • University of California, San Francisco (US)
Corresponding author
Auchus, Richard J.
ORCID
Venue
The Journal of Clinical Endocrinology & Metabolism
Publisher
The Endocrine Society
Published
1999-06-01
Volume
84
Issue
6
Pages
2104-2110
ISSN
  • 0021-972X (ISSN-L)
  • 1945-7197
DOI
10.1210/jcem.84.6.5646
OpenAlex
W2041806827
Cited by
71
References
8
Citations by year
2023: 1 · 2021: 2 · 2020: 3 · 2019: 3 · 2018: 4 · 2017: 1 · 2016: 2 · 2015: 2 · 2014: 5 · 2013: 3 · 2012: 5
FWCI
1.22
Type
journal article
Language
en
Open access
closed
Locations
  • The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Centre National de la Recherche Scientifique
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK037922, K08DK002387)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD034449)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Estrogen and related hormone effects
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal Regulation and Hypertension
Keywords
medroxyprogesterone acetate, dexamethasone, steroidogenesis inhibition, P450c17, 17α-hydroxylase/17,20-lyase, 3β-hydroxysteroid dehydrogenase, cholesterol side-chain cleavage enzyme, competitive inhibition, JEG-3 cells, adrenal steroidogenesis, progestins
MeSH terms
Animals, Anti-Inflammatory Agents, Binding, Competitive, Cholesterol Side-Chain Cleavage Enzyme, Choriocarcinoma, Dexamethasone, Enzyme Inhibitors, Humans, Kinetics, Microsomes, Multienzyme Complexes, Pregnenolone, Progesterone Reductase, Radioimmunoassay, Steroid Isomerases, Steroid 17-alpha-Hydroxylase, Steroids, Tumor Cells, Cultured, Yeasts, Medroxyprogesterone Acetate, Rats

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review