DT-Web

DB00894 - Testolactone


Identification
Name Testolactone
Accession Number DB00894 (APRD00640)
Type small molecule
Description An antineoplastic agent that is a derivative of progesterone and used to treat advanced breast cancer. [PubChem]
Structure
MOL SDF PDB SMILES InChI
Categories (*)
Molecular Weight 300.3921
Groups approved
Monoisotopic Weight 300.172544634
Pharmacology
Indication For palliative treatment of advanced breast cancer in postmenopausal women.
Mechanism of action Although the precise mechanism by which testolactone produces its clinical antineoplastic effects has not been established, its principal action is reported to be inhibition of steroid aromatase activity and consequent reduction in estrone synthesis from adrenal androstenedione, the major source of estrogen in postmenopausal women. Based on in vitro studies, the aromatase inhibition may be noncompetitive and irreversible. This phenomenon may account for the persistence of testolactone's effect on estrogen synthesis after drug withdrawal.
Absorption Testolactone is well absorbed from the gastrointestinal tract.
Protein binding ~85%
Biotransformation Hepatic. Metabolized to several derivatives in the liver, all of which preserve the lactone D-ring.
Route of elimination No clinical effects in humans of testolactone on adrenal function have been reported; however, one study noted an increase in urinary excretion of 17-ketosteroids in most of the patients treated with 150 mg/day orally. It is metabolized to several derivatives in the liver, all of which preserve the lactone D-ring. These metabolites, as well as some unmetabolized drug, are excreted in the urine.
Toxicity Oral LD50s in mouse and dog are 1630 mg/kg and 593-926 mg/kg, respectively.
Affected organisms
  • Humans and other mammals
Interactions
Drug Interactions
Drug Mechanism of interaction
Acenocoumarol The androgen, Testolactone, may incrase the anticoagulant effect of the Vitamin K antagonist, Acenocoumarol. Monitor for changes in the therapeutic effect of Acenocoumarol if Testolactone is initiated, discontinued or dose changed.
Cyclosporine The androgen, Testolactone, may increase the hepatotoxicity of Cyclosporine. Testolatone may also elevate serum concentrations of Cyclosporine. Consider alternate therapy or monitor for signs of renal and hepatic toxicity.
Warfarin Testolactone may increase the serum concentration and anticoagulant effect of warfarin. Monitor for changes in prothrombin time and therapeutic effects of warfarin if testolactone is initiated, discontinued or dose changed.
Food Interactions Not Available

Targets


Cytochrome P450 19A1
Name Cytochrome P450 19A1
Gene Name CYP19A1
Pharmacological action yes
Actions inhibitor
References
  • Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. - Pubmed
  • Raman JD, Schlegel PN: Aromatase inhibitors for male infertility. J Urol. 2002 Feb;167(2 Pt 1):624-9. - Pubmed
  • Herzog AG, Klein P, Jacobs AR: Testosterone versus testosterone and testolactone in treating reproductive and sexual dysfunction in men with epilepsy and hypogonadism. Neurology. 1998 Mar;50(3):782-4. - Pubmed
  • Dunkel L: Use of aromatase inhibitors to increase final height. Mol Cell Endocrinol. 2006 Jul 25;254-255:207-16. - Pubmed
  • Cepa MM, Tavares da Silva EJ, Correia-da-Silva G, Roleira FM, Teixeira NA: Structure-activity relationships of new A,D-ring modified steroids as aromatase inhibitors: design, synthesis, and biological activity evaluation. J Med Chem. 2005 Oct 6;48(20):6379-85. - Pubmed
DTHybrid score 0.3143

Predictions


Id Partner name Gene Name Score
146 Androgen receptor AR 0.0618
4512 Cytochrome P450 3A4 CYP3A4 0.0599
136 Estrogen receptor ESR1 0.0319
756 Sex hormone-binding globulin SHBG 0.0274
4200 Cytochrome P450 1A2 CYP1A2 0.0249
6017 Cholesterol side-chain cleavage enzyme, mitochondrial CYP11A1 0.024
260 Cytochrome P450 51 ERG11 0.0214
761 Cytochrome P450 51 ERG11 0.0214
3163 Cytochrome P450 51 cyp51 0.0214
563 Thyroid peroxidase TPO 0.0207
4116 Dihydropteroate synthetase Not Available 0.0199
226 Gonadotropin-releasing hormone receptor GNRHR 0.0193
6013 Cytochrome P450 2E1 CYP2E1 0.0191
1588 Multidrug resistance protein 1 ABCB1 0.0188
6016 Cytochrome P450 2C19 CYP2C19 0.0184
4757 Cytochrome P450 2C9 CYP2C9 0.0176
148 Lutropin-choriogonadotropic hormone receptor LHCGR 0.0175
5718 Cytochrome P450 2A6 CYP2A6 0.0167
6030 Cytochrome P450 2B6 CYP2B6 0.0163
4924 Cytochrome P450 2C8 CYP2C8 0.0152
6044 Serum paraoxonase/lactonase 3 PON3 0.0118
6107 Cytochrome P450 3A7 CYP3A7 0.0101
614 Progesterone receptor PGR 0.0096
805 Cytochrome P450 11B1, mitochondrial CYP11B1 0.0088
4118 Cytochrome P450 3A5 CYP3A5 0.0084
4119 Cytochrome P450 2D6 CYP2D6 0.0083
3941 Amine oxidase [flavin-containing] A MAOA 0.0081
871 Glucocorticoid receptor NR3C1 0.008
869 Estrogen receptor beta ESR2 0.0079
3957 Adenosine deaminase ADA 0.0079
596 3-oxo-5-alpha-steroid 4-dehydrogenase 1 SRD5A1 0.0078
1680 Solute carrier family 2, facilitated glucose transporter member 1 SLC2A1 0.0078
6024 Cytochrome P450 1A1 CYP1A1 0.0075
3923 Cholinesterase BCHE 0.0072
3939 Amine oxidase [flavin-containing] B MAOB 0.007
380 Cytochrome P450 17A1 CYP17A1 0.007
1656 CYP2B protein CYP2B 0.0068
6023 Cytochrome P450 11B2, mitochondrial CYP11B2 0.0065
1898 Cytochrome P450 1B1 CYP1B1 0.0063
1649 Small inducible cytokine A2 CCL2 0.0062
6142 Solute carrier family 22 member 8 SLC22A8 0.0062
6139 Solute carrier organic anion transporter family member 1A2 SLCO1A2 0.0061
6078 Neuronal acetylcholine receptor subunit beta-4 CHRNB4 0.006
217 Estradiol 17-beta-dehydrogenase 1 HSD17B1 0.0057
1732 ATP-binding cassette sub-family G member 2 ABCG2 0.0057
847 Mu-type opioid receptor OPRM1 0.0056
6079 Neuronal acetylcholine receptor subunit alpha-3 CHRNA3 0.0054
3947 Xanthine dehydrogenase/oxidase XDH 0.005
144 Hemoglobin subunit alpha HBA1 0.0049
3809 Estrogen-related receptor gamma ESRRG 0.0048
564 Cellular retinoic acid-binding protein 1 CRABP1 0.0047
776 Bile salt export pump ABCB11 0.0047
6020 Aldehyde oxidase AOX1 0.0047
629 Alpha-2B adrenergic receptor ADRA2B 0.0047
5934 Cytochrome P450 26A1 CYP26A1 0.0047
1010 Cytochrome P450 51A1 CYP51A1 0.0046
1178 Adenosine A2a receptor ADORA2A 0.0045
1735 Canalicular multispecific organic anion transporter 1 ABCC2 0.0043
780 Retinoic acid receptor RXR-gamma RXRG 0.0043
229 Retinoic acid receptor beta RARB 0.0043
634 Squalene monooxygenase SQLE 0.0043
7196 Squalene monooxygenase ERG1 0.0043
730 Retinoic acid receptor alpha RARA 0.0042
290 Prostaglandin G/H synthase 2 PTGS2 0.0041
872 Gamma-aminobutyric-acid receptor subunit alpha-1 GABRA1 0.004
462 Intermediate conductance calcium-activated potassium channel protein 4 KCNN4 0.004
459 Retinoic acid receptor RXR-alpha RXRA 0.004
88 Retinoic acid receptor RXR-beta RXRB 0.0039
162 Retinoic acid receptor gamma-1 RARG 0.0039
567 Receptor tyrosine-protein kinase erbB-2 ERBB2 0.0038
2782 Complement C1s subcomponent C1S 0.0037
587 Serum albumin ALB 0.0035
3815 Complement C1q subcomponent subunit A C1QA 0.0034
3816 Complement C1q subcomponent subunit B C1QB 0.0034
3817 Complement C1q subcomponent subunit C C1QC 0.0034
3818 Low affinity immunoglobulin gamma Fc region receptor III-A FCGR3A 0.0034
3819 Low affinity immunoglobulin gamma Fc region receptor II-a FCGR2A 0.0034
1102 Low affinity immunoglobulin gamma Fc region receptor III-B FCGR3B 0.0034
3821 Low affinity immunoglobulin gamma Fc region receptor II-c FCGR2C 0.0034
3814 Complement C1r subcomponent C1R 0.0034
3830 Calreticulin CALR 0.0034
3820 Low affinity immunoglobulin gamma Fc region receptor II-b FCGR2B 0.0034
474 Acetylcholinesterase ACHE 0.0033
784 High affinity immunoglobulin gamma Fc receptor I FCGR1A 0.0032
6035 Nuclear receptor ROR-beta RORB 0.0032
6034 Hydroxyindole O-methyltransferase ASMT 0.0032
6036 Eosinophil peroxidase EPX 0.0032
6025 UDP-glucuronosyltransferase 1-4 UGT1A4 0.0029
844 Epidermal growth factor receptor EGFR 0.0028
765 Indoleamine 2,3-dioxygenase IDO1 0.0027
6031 Cytochrome P450 3A43 CYP3A43 0.0027
571 Melatonin receptor type 1A MTNR1A 0.0026
362 Melatonin receptor type 1B MTNR1B 0.0026
3810 Catechol O-methyltransferase COMT 0.0025
5923 Microtubule-associated protein tau MAPT 0.0024
5924 Microtubule-associated protein 4 MAP4 0.0024
458 Neuronal acetylcholine receptor subunit alpha-10 CHRNA10 0.0023
267 Plasminogen activator inhibitor 1 SERPINE1 0.0023
20 Prostaglandin G/H synthase 1 PTGS1 0.0023
1852 Microtubule-associated protein 2 MAP2 0.0023
7 Nitric oxide synthase, inducible NOS2 0.0022
6931 Calcium-activated potassium channel subunit beta-1 KCNMB1 0.0022
6933 Calcium-activated potassium channel subunit beta-4 KCNMB4 0.0022
6932 Calcium-activated potassium channel subunit beta-3 KCNMB3 0.0022
6934 Small conductance calcium-activated potassium channel protein 1 KCNN1 0.0022
6935 Small conductance calcium-activated potassium channel protein 2 KCNN2 0.0022
6936 Small conductance calcium-activated potassium channel protein 3 KCNN3 0.0022
6143 Solute carrier family 22 member 7 SLC22A7 0.0022
273 Apoptosis regulator Bcl-2 BCL2 0.0021
373 Transthyretin TTR 0.0021
6221 Steroid hormone receptor ERR1 ESRRA 0.0021
1490 Solute carrier organic anion transporter family member 1B1 SLCO1B1 0.0021
6002 Prostaglandin E2 receptor EP4 subtype PTGER4 0.002
706 Glutamate [NMDA] receptor subunit 3A GRIN3A 0.002
243 Ribosyldihydronicotinamide dehydrogenase [quinone] NQO2 0.0019
5463 Calcium-activated potassium channel subunit beta 2 KCNMB2 0.0019
29 Tubulin beta-1 chain TUBB1 0.0019
6145 Solute carrier family 22 member 1 SLC22A1 0.0019
84 Nuclear receptor 0B1 NR0B1 0.0019
4131 Prostaglandin E2 receptor, EP3 subtype PTGER3 0.0018
1457 Long-chain-fatty-acid--CoA ligase 4 ACSL4 0.0018
406 Prostaglandin E2 receptor, EP2 subtype PTGER2 0.0018
6106 Cytochrome P450 2C18 CYP2C18 0.0018
469 Annexin A1 ANXA1 0.0018
6167 Organic solute transporter subunit beta OSTB 0.0018
6166 Organic solute transporter subunit alpha OSTA 0.0018
467 Delta-type opioid receptor OPRD1 0.0018
1192 Sulfotransferase 1A1 SULT1A1 0.0018
1284 Nuclear receptor subfamily 1 group I member 2 NR1I2 0.0018
1757 Myeloperoxidase MPO 0.0017
6104 Dimethylaniline monooxygenase [N-oxide-forming] 1 FMO1 0.0017
465 Calmodulin CALM1 0.0017
6014 Cytochrome P450 2A13 CYP2A13 0.0017
6181 UDP-glucuronosyltransferase 1-8 UGT1A8 0.0016
6148 Multidrug resistance-associated protein 7 ABCC10 0.0016
6177 UDP-glucuronosyltransferase 1-10 UGT1A10 0.0016
73 Prostaglandin E2 receptor, EP1 subtype PTGER1 0.0016
1709 Canalicular multispecific organic anion transporter 2 ABCC3 0.0016
514 Potassium voltage-gated channel subfamily H member 6 KCNH6 0.0015
772 Potassium voltage-gated channel subfamily H member 7 KCNH7 0.0015
6160 Solute carrier organic anion transporter family member 3A1 SLCO3A1 0.0015
6153 Solute carrier organic anion transporter family member 4A1 SLCO4A1 0.0015
6157 Solute carrier organic anion transporter family member 1B3 SLCO1B3 0.0014
6101 Dimethylaniline monooxygenase [N-oxide-forming] 3 FMO3 0.0014
2222 Equilibrative nucleoside transporter 1 SLC29A1 0.0014
6152 Solute carrier organic anion transporter family member 2A1 SLCO2A1 0.0014
610 Calcium-activated potassium channel subunit alpha 1 KCNMA1 0.0014
6158 Solute carrier organic anion transporter family member 1C1 SLCO1C1 0.0014
468 Cytochrome P450 4A11 CYP4A11 0.0014
6136 Multidrug resistance-associated protein 5 ABCC5 0.0013
6176 UDP-glucuronosyltransferase 1-3 UGT1A3 0.0013
6141 Sodium/bile acid cotransporter SLC10A1 0.0013
862 Multidrug resistance-associated protein 1 ABCC1 0.0013
4604 Liver carboxylesterase 1 CES1 0.0012
6018 UDP-glucuronosyltransferase 1-9 UGT1A9 0.0012
6178 UDP-glucuronosyltransferase 2B7 UGT2B7 0.0012
1632 Solute carrier organic anion transporter family member 2B1 SLCO2B1 0.0012
101 Potassium voltage-gated channel subfamily H member 2 KCNH2 0.0012
238 Peroxisome proliferator-activated receptor gamma PPARG 0.0012
6022 UDP-glucuronosyltransferase 1-1 UGT1A1 0.0012
1024 Solute carrier family 22 member 11 SLC22A11 0.0011
2164 Multidrug resistance-associated protein 4 ABCC4 0.0011
833 Organic cation/carnitine transporter 1 SLC22A4 0.0011
6147 Solute carrier family 22 member 3 SLC22A3 0.0011
291 Nitric-oxide synthase, endothelial NOS3 0.0011
6144 Solute carrier family 22 member 2 SLC22A2 0.001
1729 Solute carrier family 22 member 6 SLC22A6 0.0009
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