PDF herunterladen
Semin Reprod Med 2004; 22(4): 281-288
DOI: 10.1055/s-2004-861545
Copyright © 2004 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Overview of Dehydroepiandrosterone Biosynthesis

Richard J. Auchus1
  • 1Division of Endocrinology and Metabolism, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas
Weitere Informationen

Publikationsverlauf

Publikationsdatum:
05. Januar 2005 (online)

    Lizenzen und Reprints

ABSTRACT

The biosynthesis of dehydroepiandrosterone (DHEA) from cholesterol involves only two enzymes, both cytochrome P450s. The conversion of cholesterol to pregnenolone is mediated by cholesterol side-chain cleavage enzyme (CYP11A1), which is found in the mitochondria. The cleavage of pregnenolone to DHEA requires both the 17α-hydroxylase and 17,20-lyase activities of CYP17, which is found in the endoplasmic reticulum. These conversions require pairs of electron transfer proteins or redox partners, which are adrenodoxin and adrenodoxin reductase for CYP11A1 and cytochrome P450-oxidoreductase and cytochrome b5 for CYP17. In addition, the steroidogenic acute regulatory (StAR) protein regulates the flux of cholesterol into the biosynthetic pathway and represents the mechanism of acute regulation. Finally, in addition to possessing CYP11A1 and CYP17, it is equally important that a steroidogenic cell not contain other enzymes that drain the flux of pregnenolone to DHEA. These characteristics are illustrated by the fetal adrenal cortex and the zona reticularis, which are dedicated to the synthesis of DHEA and DHEA-sulfate.

KEYWORDS

Adrenal gland - dehydroepiandrosterone sulfate - CYP17 - 3β-hydroxysteroid dehydrogenase/Δ5/4-isomerases - cytochrome b5

REFERENCES

  • 1 Gaunt R. History of the adrenal cortex. In: Greep RO, Astwood EB Handbook of Physiology: Endocrinology. Washington, DC; American Physiological Society 1975: 1
    Google Scholar
  • 2 Baxter J D. Cortisone and the adrenal cortex. Trans Assoc Am Physicians 1987 100: clxvii
    Google Scholar
  • 3 Simpson E R. Cholesterol side-chain cleavage, cytochrome P450, and the control of steroidogenesis.  Mol Cell Endocrinol. 1979;  13 213-227
    CrossrefPubMedGoogle Scholar
  • 4 Clark B J, Wells J, King S R, Stocco D M. The purification, cloning and expression of a novel luteinizing hormone-induced mitochondrial protein in MA-10 mouse Leydig tumor cells. Characterization of the steroidogenic acute regulatory protein (StAR).  J Biol Chem. 1994;  269 28314-28322
    PubMedGoogle Scholar
  • 5 Stocco D M, Clark B J. Regulation of the acute production of steroids in steroidogenic cells.  Endocr Rev. 1996;  17 221-244
    CrossrefPubMedGoogle Scholar
  • 6 Tsujishita Y, Hurley J H. Structure and lipid transport mechanism of a StAR-related domain.  Nat Struct Biol. 2000;  7 408-414
    CrossrefPubMedGoogle Scholar
  • 7 Romanowski M J, Soccio R E, Breslow J L, Burley S K. Crystal structure of the Mus musculus cholesterol-regulated START protein 4 (StarD4) containing a StAR-related lipid transfer domain.  Proc Natl Acad Sci USA. 2002;  99 6949-6954
    CrossrefPubMedGoogle Scholar
  • 8 Lin D, Sugawara T, Strauss III J F et al.. Role of steroidogenic acute regulatory protein in adrenal and gonadal steroidogenesis.  Science. 1995;  267 1828-1831
    CrossrefPubMedGoogle Scholar
  • 9 Bose H S, Sugawara T, Strauss III J F, Miller W L. The pathophysiology and genetics of congenital lipoid adrenal hyperplasia.  N Engl J Med. 1996;  335 1870-1878
    CrossrefPubMedGoogle Scholar
  • 10 Caron K, Soo S-C, Wetsel W et al.. Targeted disruption of the mouse gene encoding steroidogenic acute regulatory protein provides insights into congenital lipoid adrenal hyperplasia.  Proc Natl Acad Sci USA. 1997;  94 11540-11545
    CrossrefPubMedGoogle Scholar
  • 11 Miller W L, Strauss III J F. Molecular pathology and mechanism of action of the steroidogenic acute regulartory protein, StAR.  J Steroid Biochem Mol Biol. 1999;  69 131-141
    CrossrefPubMedGoogle Scholar
  • 12 Shimizu K, Gut M, Dorfman R I. 20α, 22α-dihydroxycholesterol, an intermediate in the biosynthesis of pregnonolone (3β-hydroxypregn-5-en-20-one) from cholesterol.  J Biol Chem. 1962;  237 699-702
    PubMedGoogle Scholar
  • 13 Guryev O, Carvalho R A, Usanov S, Gilep A, Estabrook R W. A pathway for the metabolism of vitamin D3: unique hydroxylated metabolites formed during catalysis with cytochrome P450scc (CYP11A1).  Proc Natl Acad Sci USA. 2003;  100 14754-14759
    CrossrefPubMedGoogle Scholar
  • 14 Matteson K J, Chung B, Urdea M S, Miller W L. Study of cholesterol side chain cleavage (20,22 desmolase) deficiency causing congenital lipoid adrenal hyperplasia using bovine-sequence P450scc oligodeoxyribonucleotide probes.  Endocrinology. 1986;  118 1296-1305
    PubMedGoogle Scholar
  • 15 Chung B, Matteson K J, Voutilainen R, Mohandas T K, Miller W L. Human cholesterol side-chain cleavage enzyme, P450scc: cDNA cloning, assignment of the gene to chromosome 15, and expression in the placenta.  Proc Natl Acad Sci USA. 1986;  83 8962-8966
    PubMedGoogle Scholar
  • 16 Matocha M, Waterman M R. Synthesis and processing of mitochondrial steroid hydroxylases. In vivo maturation of the precursor of cytochrome P450scc, cytochrome P45011ß, and adrenodoxin.  J Biol Chem. 1985;  260 12259-12265
    PubMedGoogle Scholar
  • 17 Black S M, Harikrishna J A, Szklarz G D, Miller W L. The mitochondrial environment is required for activity of the cholesterol side-chain cleavage enzyme, cytochrome P450scc.  Proc Natl Acad Sci USA. 1994;  91 7247-7251
    PubMedGoogle Scholar
  • 18 John M E, John M C, Boggaram V, Simpson E R, Waterman M R. Transcriptional regulation of steroid hydroxylase genes by corticotropin.  Proc Natl Acad Sci USA. 1986;  83 4715-4719
    PubMedGoogle Scholar
  • 19 Mellon S H, Vaisse C. cAMP regulates P450scc gene expression by a cycloheximide-insensitive mechanism in cultured mouse leydig MA-10 cells.  Proc Natl Acad Sci USA. 1989;  86 7775-7779
    PubMedGoogle Scholar
  • 20 Barrett P Q, Bollag W B, Isales C M, McCarthy R T, Rasmussen H. The role of calcium in angiotensin II-mediated aldosterone secretion.  Endocr Rev. 1989;  10 496-518
    PubMedGoogle Scholar
  • 21 Yang X, Iwamoto K, Wang M et al.. Inherited congenital adrenal hyperplasia in the rabbit is caused by a deletion in the gene encoding cytochrome P450 cholesterol side-chain cleavage enzyme.  Endocrinology. 1993;  132 1977-1982
    CrossrefPubMedGoogle Scholar
  • 22 Hu M C, Hsu N C, El Hadj N B et al.. Steroid deficiency syndromes in mice with targeted disruption of Cyp11a1.  Mol Endocrinol. 2002;  16 1943-1950
    CrossrefPubMedGoogle Scholar
  • 23 Tajima T, Fujieda K, Kouda N, Nakae J, Miller W L. Heterozygous mutation in the cholesterol side chain cleavage enzyme (P450scc) gene in a patient with 46,XY sex reversal and adrenal insufficiency.  J Clin Endocrinol Metab. 2001;  86 3820-3825
    CrossrefPubMedGoogle Scholar
  • 24 Kimura T, Suzuki K. Components of the electron transport system in adrenal steroid hydroxylase. Isolation and properties of non-heme iron protein(adrenodoxin).  J Biol Chem. 1967;  242 485-491
    PubMedGoogle Scholar
  • 25 Vickery L E. Molecular recognition and electron transfer in mitochondrial steroid hydroxylase systems.  Steroids. 1997;  62 124-127
    CrossrefPubMedGoogle Scholar
  • 26 Geren L M, O'Brien P, Stonehuerner J, Millett F. Identification of specific carboxylate groups on adrenodoxin that are involved in the interaction with adrenodoxin reductase.  J Biol Chem. 1984;  259 2155-2160
    PubMedGoogle Scholar
  • 27 Coghlan V M, Vickery L E. Site-specific mutations in human ferredoxin that affect binding to ferredoxin reductase and cytochrome P450scc.  J Biol Chem. 1991;  266 18606-18612
    PubMedGoogle Scholar
  • 28 Zuber M X, Simpson E R, Waterman M R. Expression of bovine 17α-hydroxylase cytochrome P450 cDNA in non-steroidogenic (COS-1) cells.  Science. 1986;  234 1258-1261
    CrossrefPubMedGoogle Scholar
  • 29 Chung B C, Picado-Leonard J, Haniu M et al.. 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. 1987;  84 407-411
    CrossrefPubMedGoogle Scholar
  • 30 Lund J, Ahlgren R, Wu D et al.. Transcriptional regulation of the bovine CYP17 (P-45017α) gene.  J Biol Chem. 1990;  265 3304-3312
    PubMedGoogle Scholar
  • 31 Waterman M R, Simpson E R. Regulation of steroid hydroxylase gene expression is multifactorial in nature.  Recent Prog Horm Res. 1989;  45 533-566
    PubMedGoogle Scholar
  • 32 Lin C J, Martens J W, Miller W L. NF-1C, Sp1, and Sp3 are essential for transcription of the human gene for P450c17 (steroid 17α-hydroxylase/17,20 lyase) in human adrenal NCI-H295A cells.  Mol Endocrinol. 2001;  15 1277-1293
    CrossrefPubMedGoogle Scholar
  • 33 Yasukochi Y, Masters B S. Some properties of a detergent-solubilized NADPH-cytochrome c(cytochrome P-450) reductase purified by biospecific affinity chromatography.  J Biol Chem. 1976;  251 5337-5344
    PubMedGoogle Scholar
  • 34 Lee-Robichaud P, Wright J N, Akhtar M E, Akhtar M. Modulation of the activity of human 17α-hydroxylase-17,20-lyase (CYP17) by cytochrome b5: endocrinological and mechanistic implications.  Biochem J. 1995;  308 901-908
    PubMedGoogle Scholar
  • 35 Auchus R J, Lee T C, Miller W L. Cytochrome b5 augments the 17,20 lyase activity of human P450c17 without direct electron transfer.  J Biol Chem. 1998;  273 3158-3165
    CrossrefPubMedGoogle Scholar
  • 36 Flück C E, Miller W L, Auchus R J. The 17,20-lyase activity of cytochrome P450c17 from human fetal testis favors the Δ5 steroidogenic pathway.  J Clin Endocrinol Metab. 2003;  88 3762-3766
    CrossrefPubMedGoogle Scholar
  • 37 Swart P, Swart A C, Waterman M R, Estabrook R W, Mason J I. Progesterone 16α-hydroxylase activity is catalyzed by human cytochrome P450 17α-hydroxylase.  J Clin Endocrinol Metab. 1993;  77 98-102
    CrossrefPubMedGoogle Scholar
  • 38 Onoda M, Hall P F. Cytochrome b5 stimulates purified testicular microsomal cytochrome P450 (C21 side-chain cleavage).  Biochem Biophys Res Commun. 1982;  108 454-460
    CrossrefPubMedGoogle Scholar
  • 39 Katagiri M, Kagawa N, Waterman M R. The role of cytochrome b5 in the biosynthesis of androgens by human P450c17.  Arch Biochem Biophys. 1995;  317 343-347
    CrossrefPubMedGoogle Scholar
  • 40 Nakajin S, Takahashi M, Shinoda M, Hall P F. Cytochrome b5 promotes the synthesis of Δ16-C19 steroids by homogeneous cytochrome P-450 C21 side-chain cleavage from pig testis.  Biochem Biophys Res Commun. 1985;  132 708-713
    CrossrefPubMedGoogle Scholar
  • 41 Gupta M K, Guryev O L, Auchus R J. 5α-reduced C21 steroids are substrates for human cytochrome P450c17.  Arch Biochem Biophys. 2003;  418 151-160
    CrossrefPubMedGoogle Scholar
  • 42 Lee T C, Miller W L, Auchus R J. Medroxyprogesterone acetate and dexamethasone are competitive inhibitors of different human steroidogenic enzymes.  J Clin Endocrinol Metab. 1999;  84 2104-2110
    CrossrefPubMedGoogle Scholar
  • 43 Auchus R J, Kumar A S, Boswell C A et al.. The enantiomer of progesterone (ent-progesterone) is a competitive inhibitor of human cytochromes P450c17 and P450c21.  Arch Biochem Biophys. 2003;  409 134-144
    CrossrefPubMedGoogle Scholar
  • 44 Arlt W, Auchus R J, Miller W L. Thiazolidinediones but not metformin directly inhibit the steroidogenic enzymes P450c17 and 3β-hydroxysteroid dehydrogenase.  J Biol Chem. 2001;  276 16767-16771
    CrossrefPubMedGoogle Scholar
  • 45 Zhang L, Rodriguez H, Ohno S, Miller W L. Serine phosphorylation of human P450c17 increases 17,20 lyase activity: Implications for adrenarche and for the polycystic ovary syndrome.  Proc Natl Acad Sci USA. 1995;  92 10619-10623
    CrossrefPubMedGoogle Scholar
  • 46 Pandey A V, Mellon S H, Miller W L. Protein phosphatase 2A and phosphoprotein SET regulate androgen production by P450c17.  J Biol Chem. 2003;  278 2837-2844
    CrossrefPubMedGoogle Scholar
  • 47 Auchus R J. The genetics, pathophysiology, and management of human deficiencies of P450c17.  Endocrinol Metab Clin North Am. 2001;  30 101-119
    CrossrefPubMedGoogle Scholar
  • 48 Biglieri E G, Herron M A, Brust N. 17α-hydroxylation deficiency in man.  J Clin Invest. 1966;  45 1945-1954
    PubMedGoogle Scholar
  • 49 Costa-Santos M, Kater C E, Auchus R J. Two prevalent CYP17 mutations and genotype-phenotype correlations in 24 Brazilian patients with 17-hydroxylase deficiency.  J Clin Endocrinol Metab. 2004;  89 49-60
    CrossrefPubMedGoogle Scholar
  • 50 Geller D H, Auchus R J, Mendonça B B, Miller W L. The genetic and functional basis of isolated 17,20 lyase deficiency.  Nat Genet. 1997;  17 201-205
    CrossrefPubMedGoogle Scholar
  • 51 Van Den Akker E L, Koper J W, Boehmer A L et al.. Differential inhibition of 17alpha-hydroxylase and 17,20-lyase activities by three novel missense CYP17 mutations identified in patients with P450c17 deficiency.  J Clin Endocrinol Metab. 2002;  87 5714-5721
    CrossrefPubMedGoogle Scholar
  • 52 Geller D H, Auchus R J, Miller W L. P450c17 mutations R347H and R358Q selectively disrupt 17,20-lyase activity by disrupting interactions with P450 oxidoreductase and cytochrome b5 .  Mol Endocrinol. 1999;  13 167-175
    CrossrefPubMedGoogle Scholar
  • 53 Auchus R J, Miller W L. Molecular modeling of human P450c17 (17α-hydroxylase/17,20-lyase): insights into reaction mechanisms and effects of mutations.  Mol Endocrinol. 1999;  13 1169-1182
    CrossrefPubMedGoogle Scholar
  • 54 Sherbet D P, Tiosano D, Kwist K M, Hochberg Z. Auchus RJ. CYP17 mutation E305G causes isolated 17,20-lyase deficiency by selectively altering substrate binding.  J Biol Chem. 2003;  278 48563-48569
    CrossrefPubMedGoogle Scholar
  • 55 Rhéaume E, Lachance Y, Zhao H L et al.. 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. 1991;  5 1147-1157
    PubMedGoogle Scholar
  • 56 Thomas J L, Myers R P, Strickler R C. 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.  J Steroid Biochem. 1989;  33 209-217
    CrossrefPubMedGoogle Scholar
  • 57 Bongiovanni A M. The adrenogenital syndrome with deficiency of 3β-hydroxysteroid dehydrogenase.  J Clin Invest. 1962;  41 2086-2092
    CrossrefPubMedGoogle Scholar
  • 58 Moisan A M, Ricketts M L, Tardy V et al.. New insight into the molecular basis of 3β-hydroxysteroid dehydrogenase deficiency: identification of eight mutations in the HSD3β2 gene in eleven patients from seven new families and comparison of the functional properties of twenty-five mutant enzymes.  J Clin Endocrinol Metab. 1999;  84 4410-4425
    CrossrefPubMedGoogle Scholar
  • 59 Lachance Y, Luu-The V, Labrie F et al.. Characterization of human 3β-hydroxysteroid dehydrogenase/Δ5-Δ4-isomerase gene and its expression in mammalian cells.  J Biol Chem. 1990;  265 20469-20475
    PubMedGoogle Scholar
  • 60 White P C, Speiser P W. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency.  Endocr Rev. 2000;  21 245-291
    CrossrefPubMedGoogle Scholar
  • 61 Yuen B H, Mincey E K. Human chorionic gonadotropin, prolactin, estriol, and dehydroepiandrosterone sulfate concentrations in cord blood of premature and term newborn infants: relationship to the sex of the neonate.  Am J Obstet Gynecol. 1987;  156 396-400
    PubMedGoogle Scholar
  • 62 Miller W L. Steroid hormone biosynthesis and actions in the materno-feto-placental unit.  Clin Perinatol. 1998;  25 799-817
    PubMedGoogle Scholar
  • 63 de Peretti E, Pradon M, Forest M G. 17,20-desmolase deficiency in a female newborn, paradoxically virilized in utero.  J Steroid Biochem. 1984;  20 455-458
    CrossrefPubMedGoogle Scholar
  • 64 Smith M R, Rudd B T, Shirley A et al. A radioimmunoassay for the estimation of serum dehydroepiandrosterone sulphate in normal and pathological sera.  Clin Chim Acta. 1975;  65 5-13
    CrossrefPubMedGoogle Scholar
  • 65 Orentreich N, Brind J L, Rizer R L, Vogelman J H. Age changes and sex differences in serum dehydroepiandrosterone sulfate concentrations throughout adulthood.  J Clin Endocrinol Metab. 1984;  59 551-555
    CrossrefPubMedGoogle Scholar
  • 66 Auchus R J, Rainey W E. Adrenarche-physiology, biochemistry and human disease.  Clin Endocrinol (Oxf). 2004;  60 288-296
    CrossrefPubMedGoogle Scholar
  • 67 Suzuki T, Sasano H, Takeyama J et al.. Developmental changes in steroidogenic enzymes in human postnatal adrenal cortex: immunohistochemical studies.  Clin Endocrinol (Oxf). 2000;  53 739-747
    CrossrefPubMedGoogle Scholar
  • 68 Mapes S, Corbin C, Tarantal A, Conley A. The primate adrenal zona reticularis is defined by expression of cytochrome b5, 17α-hydroxylase/17,20-lyase cytochrome P450 (P450c17) and NADPH-cytochrome P450 reductase (reductase) but not 3β-hydroxysteroid dehydrogenase/Δ5-4 isomerase (3β-HSD).  J Clin Endocrinol Metab. 1999;  84 3382-3385
    CrossrefPubMedGoogle Scholar
  • 69 Dardis A, Saraco N, Rivarola M A, Belgorosky A. Decrease in the expression of the 3β-hydroxysteroid dehydrogenase gene in human adrenal tissue during prepuberty and early puberty: Implications for the mechanism of adrenarche.  Pediatr Res. 1999;  45 384-388
    PubMedGoogle Scholar
  • 70 Forbes K J, Hagen M, Glatt H, Hume  R, Coughtrie M W. Human fetal adrenal hydroxysteroid sulphotransferase: cDNA cloning, stable expression in V79 cells and functional characterisation of the expressed enzyme.  Mol Cell Endocrinol. 1995;  112 53-60
    CrossrefPubMedGoogle Scholar

Richard J AuchusM.D. Ph.D. 

5323 Harry Hines Blvd., Dallas

TX 75390-8857

eMail: richard.auchus@UTSouthwestern.edu