Hmdb loader
Record Information
Version5.0
StatusExpected but not Quantified
Creation Date2012-09-06 15:16:49 UTC
Update Date2022-03-07 02:51:40 UTC
HMDB IDHMDB0014565
Secondary Accession Numbers
  • HMDB14565
Metabolite Identification
Common NameSpironolactone
DescriptionA potassium sparing diuretic that acts by antagonism of aldosterone in the distal renal tubules. It is used mainly in the treatment of refractory edema in patients with congestive heart failure, nephrotic syndrome, or hepatic cirrhosis. Its effects on the endocrine system are utilized in the treatments of hirsutism and acne but they can lead to adverse effects. (From Martindale, The Extra Pharmacopoeia, 30th ed, p827)
Structure
Data?1582753193
Synonyms
ValueSource
EspironolactonaChEBI
SpironolactonumChEBI
SpironolattoneChEBI
AldactoneKegg
Aldactone aHMDB
AquareductHMDB
Espironolactona mundogenHMDB
FrumikalHMDB
Generosan brand OF spironolactoneHMDB
Merck dura brand OF spironolactoneHMDB
Mundogen brand OF spironolactoneHMDB
Spiro l.u.t.HMDB
SpirobetaHMDB
SpirononeHMDB
Wörwag brand OF spironolactoneHMDB
CT-Arzneimittel brand OF spironolactoneHMDB
DuraspironHMDB
Ashbourne brand OF spironolactoneHMDB
Azupharma brand OF spironolactoneHMDB
FlumachHMDB
Pfizer brand OF spironolactoneHMDB
PractonHMDB
Spirono-isisHMDB
Betapharm brand OF spironolactoneHMDB
Spiro von CTHMDB
Alphapharm brand OF spironolactoneHMDB
Alpharma brand OF spironolactoneHMDB
Alter brand OF spironolactoneHMDB
Hormosan brand OF spironolactoneHMDB
JenaspironHMDB
Mayoly-spindler brand OF spironolactoneHMDB
Novo-spirotonHMDB
Roche brand OF spironolactoneHMDB
SpiractinHMDB
SpirogammaHMDB
SpirolactoneHMDB
Spirono isisHMDB
CT Arzneimittel brand OF spironolactoneHMDB
Cardel brand OF spironolactoneHMDB
Dexo brand OF spironolactoneHMDB
Espironolactona alterHMDB
Jenapharm brand OF spironolactoneHMDB
Novo spirotonHMDB
NovoSpirotonHMDB
Novopharm brand OF spironolactoneHMDB
Pharmafrid brand OF spironolactoneHMDB
Searle brand OF spironolactoneHMDB
SpirolangHMDB
SpirospareHMDB
VeroshpironHMDB
VerospironHMDB
VerospironeHMDB
Von CT, spiroHMDB
CT, Spiro vonHMDB
Chemical FormulaC24H32O4S
Average Molecular Weight416.573
Monoisotopic Molecular Weight416.202130202
IUPAC Name(1'S,2R,2'R,9'R,10'R,11'S,15'S)-9'-(acetylsulfanyl)-2',15'-dimethylspiro[oxolane-2,14'-tetracyclo[8.7.0.0²,⁷.0¹¹,¹⁵]heptadecan]-6'-ene-5,5'-dione
Traditional Namespironolactone
CAS Registry Number52-01-7
SMILES
[H][C@@]12CC[C@@]3(CCC(=O)O3)[C@@]1(C)CC[C@@]1([H])[C@@]2([H])[C@@]([H])(CC2=CC(=O)CC[C@]12C)SC(C)=O
InChI Identifier
InChI=1S/C24H32O4S/c1-14(25)29-19-13-15-12-16(26)4-8-22(15,2)17-5-9-23(3)18(21(17)19)6-10-24(23)11-7-20(27)28-24/h12,17-19,21H,4-11,13H2,1-3H3/t17-,18-,19+,21+,22-,23-,24+/m0/s1
InChI KeyLXMSZDCAJNLERA-ZHYRCANASA-N
Chemical Taxonomy
Description Belongs to the class of organic compounds known as spironolactones and derivatives. These are steroid lactones with a structure based on the spironolactone skeleton.
KingdomOrganic compounds
Super ClassLipids and lipid-like molecules
ClassSteroids and steroid derivatives
Sub ClassSteroid lactones
Direct ParentSpironolactones and derivatives
Alternative Parents
Substituents
  • Spironolactone
  • 3-oxo-delta-4-steroid
  • 3-oxosteroid
  • Oxosteroid
  • Delta-4-steroid
  • Cyclohexenone
  • Gamma butyrolactone
  • Tetrahydrofuran
  • Carboxylic acid ester
  • Carbothioic s-ester
  • Cyclic ketone
  • Thiocarboxylic acid ester
  • Ketone
  • Lactone
  • Oxacycle
  • Carboxylic acid derivative
  • Organoheterocyclic compound
  • Sulfenyl compound
  • Thiocarboxylic acid or derivatives
  • Monocarboxylic acid or derivatives
  • Organic oxygen compound
  • Carbonyl group
  • Organic oxide
  • Hydrocarbon derivative
  • Organooxygen compound
  • Organosulfur compound
  • Aliphatic heteropolycyclic compound
Molecular FrameworkAliphatic heteropolycyclic compounds
External Descriptors
Ontology
Not AvailableNot Available
Physical Properties
StateSolid
Experimental Molecular Properties
PropertyValueReference
Melting Point134.5 °CNot Available
Boiling PointNot AvailableNot Available
Water Solubility0.002 g/LNot Available
LogP3.4Not Available
Experimental Chromatographic PropertiesNot Available
Predicted Molecular Properties
PropertyValueSource
Water Solubility0.002 g/LALOGPS
logP3.1ALOGPS
logP3.64ChemAxon
logS-5.3ALOGPS
pKa (Strongest Acidic)18.01ChemAxon
pKa (Strongest Basic)-4.9ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area60.44 ŲChemAxon
Rotatable Bond Count2ChemAxon
Refractivity113.5 m³·mol⁻¹ChemAxon
Polarizability46.03 ųChemAxon
Number of Rings5ChemAxon
BioavailabilityYesChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted Chromatographic Properties

Predicted Collision Cross Sections

PredictorAdduct TypeCCS Value (Å2)Reference
DarkChem[M+H]+197.81931661259
DarkChem[M-H]-188.7431661259
DeepCCS[M-2H]-242.82330932474
DeepCCS[M+Na]+217.39630932474
AllCCS[M+H]+200.932859911
AllCCS[M+H-H2O]+198.832859911
AllCCS[M+NH4]+202.932859911
AllCCS[M+Na]+203.432859911
AllCCS[M-H]-204.032859911
AllCCS[M+Na-2H]-204.832859911
AllCCS[M+HCOO]-205.832859911

Predicted Kovats Retention Indices

Underivatized

MetaboliteSMILESKovats RI ValueColumn TypeReference
Spironolactone[H][C@@]12CC[C@@]3(CCC(=O)O3)[C@@]1(C)CC[C@@]1([H])[C@@]2([H])[C@@]([H])(CC2=CC(=O)CC[C@]12C)SC(C)=O4350.6Standard polar33892256
Spironolactone[H][C@@]12CC[C@@]3(CCC(=O)O3)[C@@]1(C)CC[C@@]1([H])[C@@]2([H])[C@@]([H])(CC2=CC(=O)CC[C@]12C)SC(C)=O3297.5Standard non polar33892256
Spironolactone[H][C@@]12CC[C@@]3(CCC(=O)O3)[C@@]1(C)CC[C@@]1([H])[C@@]2([H])[C@@]([H])(CC2=CC(=O)CC[C@]12C)SC(C)=O3799.5Semi standard non polar33892256

Derivatized

Derivative Name / StructureSMILESKovats RI ValueColumn TypeReference
Spironolactone,1TMS,isomer #1CC(=O)S[C@@H]1CC2=CC(O[Si](C)(C)C)=CC[C@]2(C)[C@H]2CC[C@@]3(C)[C@@H](CC[C@@]34CCC(=O)O4)[C@@H]213468.4Semi standard non polar33892256
Spironolactone,1TMS,isomer #1CC(=O)S[C@@H]1CC2=CC(O[Si](C)(C)C)=CC[C@]2(C)[C@H]2CC[C@@]3(C)[C@@H](CC[C@@]34CCC(=O)O4)[C@@H]213345.4Standard non polar33892256
Spironolactone,1TMS,isomer #1CC(=O)S[C@@H]1CC2=CC(O[Si](C)(C)C)=CC[C@]2(C)[C@H]2CC[C@@]3(C)[C@@H](CC[C@@]34CCC(=O)O4)[C@@H]213908.5Standard polar33892256
Spironolactone,1TBDMS,isomer #1CC(=O)S[C@@H]1CC2=CC(O[Si](C)(C)C(C)(C)C)=CC[C@]2(C)[C@H]2CC[C@@]3(C)[C@@H](CC[C@@]34CCC(=O)O4)[C@@H]213707.4Semi standard non polar33892256
Spironolactone,1TBDMS,isomer #1CC(=O)S[C@@H]1CC2=CC(O[Si](C)(C)C(C)(C)C)=CC[C@]2(C)[C@H]2CC[C@@]3(C)[C@@H](CC[C@@]34CCC(=O)O4)[C@@H]213576.1Standard non polar33892256
Spironolactone,1TBDMS,isomer #1CC(=O)S[C@@H]1CC2=CC(O[Si](C)(C)C(C)(C)C)=CC[C@]2(C)[C@H]2CC[C@@]3(C)[C@@H](CC[C@@]34CCC(=O)O4)[C@@H]214035.9Standard polar33892256
Spectra

GC-MS Spectra

Spectrum TypeDescriptionSplash KeyDeposition DateSourceView
Predicted GC-MSPredicted GC-MS Spectrum - Spironolactone GC-MS (Non-derivatized) - 70eV, Positivesplash10-0h2u-0109000000-b5dcae38bb499eaabba72017-09-01Wishart LabView Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - Spironolactone GC-MS (Non-derivatized) - 70eV, PositiveNot Available2021-10-12Wishart LabView Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - Spironolactone GC-MS (Non-derivatized) - 70eV, PositiveNot Available2021-10-12Wishart LabView Spectrum
MSMass Spectrum (Electron Ionization)splash10-0006-9836000000-9f600bd39c3b914c0b172014-09-20Not AvailableView Spectrum

MS/MS Spectra

Spectrum TypeDescriptionSplash KeyDeposition DateSourceView
Experimental LC-MS/MSLC-MS/MS Spectrum - Spironolactone LC-ESI-ITFT , positive-QTOFsplash10-014i-0000900000-5e2e1944e45fcef225d12017-09-14HMDB team, MONAView Spectrum
Experimental LC-MS/MSLC-MS/MS Spectrum - Spironolactone LC-ESI-ITFT , positive-QTOFsplash10-014i-0000900000-406c100eed5b6cdc32862017-09-14HMDB team, MONAView Spectrum
Experimental LC-MS/MSLC-MS/MS Spectrum - Spironolactone 15V, Positive-QTOFsplash10-014i-0000900000-406c100eed5b6cdc32862021-09-20HMDB team, MONAView Spectrum
Experimental LC-MS/MSLC-MS/MS Spectrum - Spironolactone 15V, Positive-QTOFsplash10-014i-0000900000-5e2e1944e45fcef225d12021-09-20HMDB team, MONAView Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - Spironolactone 10V, Positive-QTOFsplash10-00or-0009200000-27849e6f24a460d7ac902016-06-03Wishart LabView Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - Spironolactone 20V, Positive-QTOFsplash10-05mn-0129000000-5819587c9e746750f5c02016-06-03Wishart LabView Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - Spironolactone 40V, Positive-QTOFsplash10-01tl-0192000000-6a35fab760c0aa7327232016-06-03Wishart LabView Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - Spironolactone 10V, Negative-QTOFsplash10-00xr-0009200000-defcf21ed513948675a32016-08-03Wishart LabView Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - Spironolactone 20V, Negative-QTOFsplash10-00di-1009000000-ebe97ba9dd52376b449f2016-08-03Wishart LabView Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - Spironolactone 40V, Negative-QTOFsplash10-0006-9004000000-2eccefa334bd23b4cdc12016-08-03Wishart LabView Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - Spironolactone 10V, Positive-QTOFsplash10-014i-0002900000-f73d8e9df6c71e49d6eb2021-09-22Wishart LabView Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - Spironolactone 20V, Positive-QTOFsplash10-0uy1-0569200000-db11732abcc12259a54d2021-09-22Wishart LabView Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - Spironolactone 40V, Positive-QTOFsplash10-0ukc-4593000000-33eba50454259079f6052021-09-22Wishart LabView Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - Spironolactone 10V, Negative-QTOFsplash10-014i-0001900000-329d630008c4558a5ec52021-09-23Wishart LabView Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - Spironolactone 20V, Negative-QTOFsplash10-00xr-7009500000-69af52e904d20a0c7b9b2021-09-23Wishart LabView Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - Spironolactone 40V, Negative-QTOFsplash10-00di-8009000000-ba8deb5a673f3bd4868e2021-09-23Wishart LabView Spectrum
Biological Properties
Cellular Locations
  • Cytoplasm
  • Extracellular
  • Membrane
Biospecimen Locations
  • Blood
  • Urine
Tissue LocationsNot Available
Pathways
Normal Concentrations
BiospecimenStatusValueAgeSexConditionReferenceDetails
BloodExpected but not QuantifiedNot QuantifiedNot AvailableNot AvailableTaking drug identified by DrugBank entry DB00421 details
UrineExpected but not QuantifiedNot QuantifiedNot AvailableNot AvailableTaking drug identified by DrugBank entry DB00421 details
Abnormal Concentrations
Not Available
Predicted Concentrations
BiospecimenValueOriginal ageOriginal sexOriginal conditionComments
Blood0.000 uMAdult (>18 years old)BothNormalPredicted based on drug qualities
Blood0.000 umol/mmol creatinineAdult (>18 years old)BothNormalPredicted based on drug qualities
Associated Disorders and Diseases
Disease ReferencesNone
Associated OMIM IDsNone
DrugBank IDDB00421
Phenol Explorer Compound IDNot Available
FooDB IDFDB006238
KNApSAcK IDNot Available
Chemspider ID5628
KEGG Compound IDC07310
BioCyc IDNot Available
BiGG IDNot Available
Wikipedia LinkSpironolactone
METLIN IDNot Available
PubChem Compound5833
PDB IDSNL
ChEBI ID9241
Food Biomarker OntologyNot Available
VMH IDNot Available
MarkerDB IDNot Available
Good Scents IDNot Available
References
Synthesis ReferenceNot Available
Material Safety Data Sheet (MSDS)Download (PDF)
General References
  1. Wandelt-Freerksen E: [Aldactone in the treatment of sarcoidosis of the lungs (author's transl)]. Z Erkr Atmungsorgane. 1977 Jul;149(1):156-9. [PubMed:607621 ]
  2. Berardesca E, Gabba P, Ucci G, Borroni G, Rabbiosi G: Topical spironolactone inhibits dihydrotestosterone receptors in human sebaceous glands: an autoradiographic study in subjects with acne vulgaris. Int J Tissue React. 1988;10(2):115-9. [PubMed:2972662 ]
  3. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J: The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999 Sep 2;341(10):709-17. [PubMed:10471456 ]
  4. Simons K, Toomre D: Lipid rafts and signal transduction. Nat Rev Mol Cell Biol. 2000 Oct;1(1):31-9. [PubMed:11413487 ]
  5. Watson AD: Thematic review series: systems biology approaches to metabolic and cardiovascular disorders. Lipidomics: a global approach to lipid analysis in biological systems. J Lipid Res. 2006 Oct;47(10):2101-11. Epub 2006 Aug 10. [PubMed:16902246 ]
  6. Sethi JK, Vidal-Puig AJ: Thematic review series: adipocyte biology. Adipose tissue function and plasticity orchestrate nutritional adaptation. J Lipid Res. 2007 Jun;48(6):1253-62. Epub 2007 Mar 20. [PubMed:17374880 ]
  7. Lingwood D, Simons K: Lipid rafts as a membrane-organizing principle. Science. 2010 Jan 1;327(5961):46-50. doi: 10.1126/science.1174621. [PubMed:20044567 ]
  8. Gunstone, Frank D., John L. Harwood, and Albert J. Dijkstra (2007). The lipid handbook with CD-ROM. CRC Press.

Enzymes

General function:
Involved in monooxygenase activity
Specific function:
Has steroid 11-beta-hydroxylase activity. In addition to this activity, the 18 or 19-hydroxylation of steroids and the aromatization of androstendione to estrone have also been ascribed to cytochrome P450 XIB.
Gene Name:
CYP11B1
Uniprot ID:
P15538
Molecular weight:
57572.44
References
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256 ]
General function:
Involved in monooxygenase activity
Specific function:
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. In the epoxidation of arachidonic acid it generates only 14,15- and 11,12-cis-epoxyeicosatrienoic acids. It is the principal enzyme responsible for the metabolism the anti-cancer drug paclitaxel (taxol).
Gene Name:
CYP2C8
Uniprot ID:
P10632
Molecular weight:
55824.275
References
  1. Walsky RL, Gaman EA, Obach RS: Examination of 209 drugs for inhibition of cytochrome P450 2C8. J Clin Pharmacol. 2005 Jan;45(1):68-78. [PubMed:15601807 ]
  2. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256 ]
General function:
Involved in DNA binding
Specific function:
Steroid hormone receptors are ligand-activated transcription factors that regulate eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Transcription factor activity is modulated by bound coactivator and corepressor proteins. Transcription activation is down-regulated by NR0B2. Activated, but not phosphorylated, by HIPK3
Gene Name:
AR
Uniprot ID:
P10275
Molecular weight:
98987.9
References
  1. Ye P, Yamashita T, Pollock DM, Sasano H, Rainey WE: Contrasting effects of eplerenone and spironolactone on adrenal cell steroidogenesis. Horm Metab Res. 2009 Jan;41(1):35-9. doi: 10.1055/s-0028-1087188. Epub 2008 Sep 25. [PubMed:18819053 ]
General function:
Involved in sequence-specific DNA binding transcription factor activity
Specific function:
Receptor for both mineralocorticoids (MC) such as aldosterone and glucocorticoids (GC) such as corticosterone or cortisol. Binds to mineralocorticoid response elements (MRE) and transactivates target genes. The effect of MC is to increase ion and water transport and thus raise extracellular fluid volume and blood pressure and lower potassium levels
Gene Name:
NR3C2
Uniprot ID:
P08235
Molecular weight:
107066.6
References
  1. Sitruk-Ware R: Progestogens in hormonal replacement therapy: new molecules, risks, and benefits. Menopause. 2002 Jan-Feb;9(1):6-15. [PubMed:11791081 ]
  2. Rogerson FM, Yao YZ, Smith BJ, Dimopoulos N, Fuller PJ: Determinants of spironolactone binding specificity in the mineralocorticoid receptor. J Mol Endocrinol. 2003 Dec;31(3):573-82. [PubMed:14664717 ]
  3. Gertner RA, Klein JD, Bailey JL, Kim DU, Luo XH, Bagnasco SM, Sands JM: Aldosterone decreases UT-A1 urea transporter expression via the mineralocorticoid receptor. J Am Soc Nephrol. 2004 Mar;15(3):558-65. [PubMed:14978157 ]
  4. Frishman WH, Stier CT Jr: Aldosterone and aldosterone antagonism in systemic hypertension. Curr Hypertens Rep. 2004 Jun;6(3):195-200. [PubMed:15128471 ]
  5. Rogerson FM, Yao Y, Smith BJ, Fuller PJ: Differences in the determinants of eplerenone, spironolactone and aldosterone binding to the mineralocorticoid receptor. Clin Exp Pharmacol Physiol. 2004 Oct;31(10):704-9. [PubMed:15554912 ]
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352 ]
  7. Sica DA: Pharmacokinetics and pharmacodynamics of mineralocorticoid blocking agents and their effects on potassium homeostasis. Heart Fail Rev. 2005 Jan;10(1):23-9. [PubMed:15947888 ]
  8. Rossi G, Boscaro M, Ronconi V, Funder JW: Aldosterone as a cardiovascular risk factor. Trends Endocrinol Metab. 2005 Apr;16(3):104-7. [PubMed:15808807 ]

Transporters

General function:
Involved in ATP binding
Specific function:
Mediates hepatobiliary excretion of numerous organic anions. May function as a cellular cisplatin transporter
Gene Name:
ABCC2
Uniprot ID:
Q92887
Molecular weight:
174205.6
References
  1. Johnson DR, Klaassen CD: Regulation of rat multidrug resistance protein 2 by classes of prototypical microsomal enzyme inducers that activate distinct transcription pathways. Toxicol Sci. 2002 Jun;67(2):182-9. [PubMed:12011477 ]
General function:
Involved in ATP binding
Specific function:
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells
Gene Name:
ABCB1
Uniprot ID:
P08183
Molecular weight:
141477.3
References
  1. Wang E, Lew K, Barecki M, Casciano CN, Clement RP, Johnson WW: Quantitative distinctions of active site molecular recognition by P-glycoprotein and cytochrome P450 3A4. Chem Res Toxicol. 2001 Dec;14(12):1596-603. [PubMed:11743742 ]
General function:
Involved in transporter activity
Specific function:
Mediates the Na(+)-independent transport of organic anions such as sulfobromophthalein (BSP) and conjugated (taurocholate) and unconjugated (cholate) bile acids
Gene Name:
SLCO1A2
Uniprot ID:
P46721
Molecular weight:
74144.1
References
  1. Kanai N, Lu R, Bao Y, Wolkoff AW, Schuster VL: Transient expression of oatp organic anion transporter in mammalian cells: identification of candidate substrates. Am J Physiol. 1996 Feb;270(2 Pt 2):F319-25. [PubMed:8779893 ]