Thalidomide

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Identification

Summary

Thalidomide is a medication used to treat cancers, particularly newly diagnosed multiple myeloma, and erythema nodosum leprosum.

Brand Names

Thalomid

Generic Name

Thalidomide

DrugBank Accession Number

DB01041

Background

A piperidinyl isoindole originally introduced as a non-barbiturate hypnotic, thalidomide was withdrawn from the market due to teratogenic effects. It has been reintroduced and used for a number of inflammatory disorders and cancers. Thalidomide displays immunosuppressive and anti-angiogenic activity through modulating the release of inflammatory mediators like tumor necrosis factor-alpha (TNF-a) and other cytokine action. Due to severe teratogenicity, pregnancy must be excluded before the start of treatment and patients must enrol in the THALIDOMID Risk Evaluation and Mitigation Strategy (REMS) program to ensure contraception adherence.¹⁰

Type

Small Molecule

Groups

Approved, Investigational, Withdrawn

Structure

Similar Structures

Weight: Average: 258.2295
Monoisotopic: 258.064056818
Chemical Formula: C₁₃H₁₀N₂O₄

Synonyms

(+-)-N-(2,6-dioxo-3-Piperidyl)phthalimide
(+-)-Thalidomide
(±)-N-(2,6-dioxo-3-piperidyl)phthalimide
(±)-thalidomide
1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)isoindoline
2,6-dioxo-3-phthalimidopiperidine
3-Phthalimidoglutarimide
alpha-(N-Phthalimido)glutarimide
alpha-N-Phthalylglutaramide
N-(2,6-dioxo-3-piperidyl)phthalimide
N-Phthaloylglutamimide
N-Phthalyl-glutaminsaeure-imid
N-Phthalylglutamic acid imide
Talidomida
Thalidomide
Thalidomidum
α-(N-phthalimido)glutarimide
α-N-phthalylglutaramide
α-phthalimidoglutarimide

External IDs

NSC-527179
NSC-66847

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Pharmacology

Indication

Thalidomide is primarily used for the acute treatment and maintenance therapy to prevent and suppress the cutaneous manifestations of moderate to severe erythema nodosum leprosum (ENL).¹⁰

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Dose Form
Treatment of	Aphthous stomatitis		••• •••••	•••••••
Treatment of	Chronic graft-versus-host disease		••• •••••	•••••••
Prevention of	Erythema nodosum leprosum		••••••••••••	•••••••
Used in combination to manage	Light-chain amyloidosis	Regimen in combination with: Dexamethasone (DB01234), Cyclophosphamide (DB00531)	••• •••••	•••••••
Used in combination to treat	Multiple myeloma	Regimen in combination with: Dexamethasone (DB01234)	••••••••••••	•••••••

Contraindications & Blackbox Warnings

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Pharmacodynamics

Thalidomide, originally developed as a sedative, is an immunomodulatory and anti-inflammatory agent with a spectrum of activity that is not fully characterized. However, thalidomide is believed to exert its effect through inhibiting and modulating the level of various inflammatory mediators, particularly tumor necrosis factor-alpha (TNF-a) and IL-6. ⁵ Additionally, thalidomide is also shown to inhibit basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), suggesting a potential anti-angiogenic application of thalidomide in cancer patients. ⁶

Thalidomide is racemic — it contains both left and right handed isomers in equal amounts: the (+)R enantiomer is effective against morning sickness, and the (−)S enantiomer is teratogenic. The enantiomers are interconverted to each other in vivo; hence, administering only one enantiomer will not prevent the teratogenic effect in humans ⁷.

Mechanism of action

The mechanism of action of thalidomide is not fully understood. Previous research indicate that thalidomide binds to cerebron, a component of the E3 ubiquitin ligase complex, to selectively degrade the transcription factor IKZF3 and IKZF1. These 2 transcription factors are vital for the proliferation and survival of malignant myeloma cells. ²

Regarding TNF-alpha, thalidomide seems to block this mediator via a variety of mechanism. Thalidomide can inhibit the expression myeloid differentiating factor 88 (MyD88), an adaptor protein that is involved in the TNF-alpha production signalling pathway, at the protein and RNA level. Additionally, thalidomide prevents the activation of Nuclear Factor Kappa B (NF-kB), another upstream effector of the TNF-alpha production pathway. Finally, some evidences suggest that thalidomide can block alpha-1 acid glycoprotein (AGP), a known inducer of the NF-kB/MyD88 pathway, thus inhibiting the expression of TNF-alpha ⁸. The down-regulation of NF-kB and MyD88 can also affect the cross talk between the NF-kB/MyD88 and VEGF pathway, resulting in thalidomide's anti-angiogenic effect. ⁹

Target	Actions	Organism
ATumor necrosis factor	inhibitor	Humans
AProtein cereblon	inhibitor	Humans
ADNA	intercalation	Humans
Aalpha1-acid glycoprotein	binder	Humans

Absorption

The absolute bioavailability has not yet been characterized in human subjects due to its poor aqueous solubility. The mean time to peak plasma concentrations (T_max) ranged from 2.9 to 5.7 hours following a single dose from 50 to 400 mg. Patients with Hansen’s disease may have an increased bioavailability of thalidomide, although the clinical significance of this is unknown. ¹⁰

Due to its low aqueous solubility and thus low dissolution is the gastrointestinal tract, thalidomide's absorption is slow, with a t_lag of 20-40 min. Therefore, thalidomide exhibits absorption rate-limited pharmacokinetics or "flip-flop" phenomenon. Following a single dose of 200 mg in healthy male subjects, c_max and AUC_∞ were calculated to be 2.00 ± 0.55 mg/L and 19.80 ± 3.61 mg*h/mL respectively. ⁴

Volume of distribution

The volume of distribution of thalidomide is difficult to determine due to spontaneous hydrolysis and chiral inversion, but it is estimated to be 70-120 L. ^4,1

Protein binding

The mean plasma protein binding is 55% and 66% for the (+)R and (−)S enantiomers, respectively. ¹⁰

Metabolism

Thalidomide appears to undergo primarily non-enzymatic hydrolysis in plasma to multiple metabolites, as the four amide bonds in thalidomide allow for rapid hydrolysis under physiological pH. ³

Evidences for enzymatic metabolism of thalidomide is mixed, as in vitro studies using rat liver microsome have detected 5-hydroxythalidomide (5-OH), a monohydroxylated metabolite of thalidomide catalyzed by the CYP2C19 enzyme, and the addition of omeprazole, a CYP2C19 inhibitor, inhibits the metabolism of thalidomide. ³ 5-hydroxythalidomide (5-OH) has also been detected in the plasma of 32% of androgen-independent prostate cancer patients undergoing oral thalidomide treatment.³ However, significant interspecies difference in thalidomide metabolism has been noted, potentially signifying that animals like rats and rabbits rely on enzymatic metabolism of thalidomide more than human.³

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Thalidomide

Route of elimination

Thalidomide is primarily excreted in urine as hydrolytic metabolites since less than 1% of the parent form is detected in the urine. Fecal excretion of thalidomide is minimal. ¹⁰

Half-life

The half-life of thalidomide in healthy male subjects after a single dose of 200 mg is 6.17 ± 2.56 h. ³

Clearance

The oral clearance of thalidomide is 10.50 ± 2.10 L/h. ³

Adverse Effects

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Toxicity

The oral LD₅₀ in rats is 113 mg/kg and 2 g/kg in mouse.¹¹

Two-year carcinogenicity studies were conducted in male and female rats and mice. No compound-related tumorigenic effects were observed at the highest dose levels of 3,000 mg/kg/day to male and female mice (38-fold greater than the highest recommended daily human dose of 400 mg based upon body surface area [BSA]), 3,000 mg/kg/day to female rats (75-fold the maximum human dose based upon BSA), and 300 mg/kg/day to male rats (7.5-fold the maximum human dose based upon BSA). ¹⁰

Thalidomide was neither mutagenic nor genotoxic in the following assays: the Ames bacterial (S. typhimurium and E. coli) reverse mutation assay, a Chinese hamster ovary cell (AS52/XPRT) forward mutation assay, and an in vivo mouse micronucleus test. ¹⁰

Fertility studies were conducted in male and female rabbits; no compound-related effects in mating and fertility indices were observed at any oral thalidomide dose level including the highest of 100 mg/kg/day to female rabbits and 500 mg/kg/day to male rabbits (approximately 5- and 25- fold the maximum human dose, respectively, based upon BSA). Testicular pathological and histopathological effects (classified as slight) were seen in male rabbits at dose levels ≥30 mg/kg/day (approximately 1.5-fold the maximum human dose based upon BSA). ¹⁰

There is no specific antidote for a thalidomide overdose. In the event of an overdose, the patient’s vital signs should be monitored and appropriate supportive care given to maintain blood pressure and respiratory status. ¹⁰

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Not Available

Interactions

Drug Interactions

This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

Drug	Interaction
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1,2-Benzodiazepine	1,2-Benzodiazepine may increase the central nervous system depressant (CNS depressant) activities of Thalidomide.
Abaloparatide	The risk or severity of adverse effects can be increased when Thalidomide is combined with Abaloparatide.
Abametapir	The serum concentration of Thalidomide can be increased when it is combined with Abametapir.
Abatacept	The metabolism of Thalidomide can be increased when combined with Abatacept.
Abciximab	The risk or severity of bleeding can be increased when Abciximab is combined with Thalidomide.

Food Interactions

Avoid alcohol. Ingesting alcohol may increase the drowsiness caused by thalidomide.
Take after a meal. Wait at least 1 hour after eating before taking thalidomide.

Products

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International/Other Brands

Contergan / Distaval / K-17 / Pro-ban M / Sedalis / Softenon / Talimol / Thaled

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Thalidomide Celgene	Capsule	50 mg	Oral	Bristol Myers Squibb Pharma Eeig	2016-09-08	Not applicable
Thalidomide Lipomed	Tablet, coated	100 mg	Oral	Lipomed	2022-12-02	Not applicable
Thalomid	Capsule	50 mg	Oral	Bristol Myers Squibb	2010-11-01	Not applicable
Thalomid	Capsule	100 mg	Oral	Bristol Myers Squibb	2011-02-17	Not applicable
Thalomid	Capsule	100 mg/1	Oral	Celgene Corporation	2003-06-20	Not applicable

Chemical Identifiers

UNII: 4Z8R6ORS6L
CAS number: 50-35-1
InChI Key: UEJJHQNACJXSKW-UHFFFAOYSA-N
InChI: InChI=1S/C13H10N2O4/c16-10-6-5-9(11(17)14-10)15-12(18)7-3-1-2-4-8(7)13(15)19/h1-4,9H,5-6H2,(H,14,16,17)
IUPAC Name: 2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione
SMILES: O=C1N(C2CCC(=O)NC2=O)C(=O)C2=CC=CC=C12

References

Synthesis Reference

Jamshed Shah, "Synthesis and anti-tumor activity of nitrogen substituted thalidomide analogs." U.S. Patent US20030139451, issued July 24, 2003.

US20030139451

General References

Eriksson T, Bjorkman S, Hoglund P: Clinical pharmacology of thalidomide. Eur J Clin Pharmacol. 2001 Aug;57(5):365-76. doi: 10.1007/s002280100320. [Article]
Kronke J, Udeshi ND, Narla A, Grauman P, Hurst SN, McConkey M, Svinkina T, Heckl D, Comer E, Li X, Ciarlo C, Hartman E, Munshi N, Schenone M, Schreiber SL, Carr SA, Ebert BL: Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science. 2014 Jan 17;343(6168):301-5. doi: 10.1126/science.1244851. Epub 2013 Nov 29. [Article]
Lepper ER, Smith NF, Cox MC, Scripture CD, Figg WD: Thalidomide metabolism and hydrolysis: mechanisms and implications. Curr Drug Metab. 2006 Aug;7(6):677-85. doi: 10.2174/138920006778017777. [Article]
Teo SK, Colburn WA, Tracewell WG, Kook KA, Stirling DI, Jaworsky MS, Scheffler MA, Thomas SD, Laskin OL: Clinical pharmacokinetics of thalidomide. Clin Pharmacokinet. 2004;43(5):311-27. doi: 10.2165/00003088-200443050-00004. [Article]
Anderson KC: Lenalidomide and thalidomide: mechanisms of action--similarities and differences. Semin Hematol. 2005 Oct;42(4 Suppl 4):S3-8. [Article]
Baidas S, Tfayli A, Bhargava P: Thalidomide: an old drug with new clinical applications. Cancer Invest. 2002;20(5-6):835-48. doi: 10.1081/cnv-120002498. [Article]
Tokunaga E, Yamamoto T, Ito E, Shibata N: Understanding the Thalidomide Chirality in Biological Processes by the Self-disproportionation of Enantiomers. Sci Rep. 2018 Nov 20;8(1):17131. doi: 10.1038/s41598-018-35457-6. [Article]
Majumder S, Sreedhara SR, Banerjee S, Chatterjee S: TNF alpha signaling beholds thalidomide saga: a review of mechanistic role of TNF-alpha signaling under thalidomide. Curr Top Med Chem. 2012;12(13):1456-67. doi: 10.2174/156802612801784443. [Article]
Sherbet GV: Therapeutic Potential of Thalidomide and Its Analogues in the Treatment of Cancer. Anticancer Res. 2015 Nov;35(11):5767-72. [Article]
FDA Approved Drug Products: Thalidomid (thalidomide) capsules for oral use [Link]
Cayman Chemical: Thalidomide MSDS [Link]
Health Canada Approved Drug Proucts: Thalidomid (thalidomide) capsules for oral use [Link]

External Links

Human Metabolome Database: HMDB0015175
KEGG Drug: D00754
KEGG Compound: C07910
PubChem Compound: 5426
PubChem Substance: 46505665
ChemSpider: 5233
BindingDB: 50070114
RxNav: 10432
ChEBI: 74947
ChEMBL: CHEMBL468
Therapeutic Targets Database: DAP000865
PharmGKB: PA451644
RxList: RxList Drug Page
Drugs.com: Drugs.com Drug Page
Wikipedia: Thalidomide

FDA label

Download (180 KB)

MSDS

Download (58.6 KB)

Clinical Trials

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Phase	Status	Purpose	Conditions	Count	Start Date	Why Stopped	100+ additional columns
Unlock 175K+ rows when you subscribe.View sample data
Not Available	Completed	Other	Multiple Myeloma (MM)	1	somestatus	stop reason	just information to hide
Not Available	Completed	Prevention	Blood Diseases / Bone Marrow Transplant (BMT) / Graft-versus-host Disease (GVHD) / Hematopoietic Stem Cell Transplantation (SCT) / Leukemias / Multiple Myeloma (MM) / Myelodysplastic Syndrome	1	somestatus	stop reason	just information to hide
Not Available	Completed	Supportive Care	Multiple Myeloma (MM)	1	somestatus	stop reason	just information to hide
Not Available	Completed	Treatment	Adrenoleukodystrophy (ALD)	1	somestatus	stop reason	just information to hide
Not Available	Completed	Treatment	HIV Wasting Syndrome / Human Immunodeficiency Virus (HIV) Infections	1	somestatus	stop reason	just information to hide

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Celgene
IDT Australia Ltd.
Penn Pharmaceutical Services Ltd.

Dosage Forms

Form	Route	Strength
Tablet	Oral	100.000 mg
Tablet, film coated	Oral	100 mg
Tablet, coated	Oral	100 mg
Capsule	Oral	100 mg/1
Capsule	Oral	100 mg
Capsule	Oral	150 mg
Capsule	Oral	150 mg/1
Capsule	Oral	200 mg
Capsule	Oral	200 mg/1
Capsule	Oral	50 mg/1
Capsule	Oral	50 mg

Prices

Unit description	Cost	Unit
Thalomid 28 50 mg capsule Disp Pack	4372.47USD	disp
Thalomid 200 mg capsule	277.5USD	capsule
Thalomid 150 mg capsule	260.61USD	capsule
Thalomid 100 mg capsule	243.73USD	capsule
Thalomid 50 mg capsule	150.15USD	capsule

DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)
US6235756	No	2001-05-22	2013-03-01
CA2505964	No	2009-07-28	2023-11-13
CA2157288	No	2005-11-08	2014-02-24
US6045501	No	2000-04-04	2018-08-28
US6315720	No	2001-11-13	2020-10-23
US6561976	No	2003-05-13	2018-08-28
US6561977	No	2003-05-13	2020-10-23
US6755784	No	2004-06-29	2020-10-23
US6869399	No	2005-03-22	2020-10-23
US6908432	No	2005-06-21	2018-08-28
US7141018	No	2006-11-28	2020-10-23
US7435745	No	2008-10-14	2017-11-03
US7874984	No	2011-01-25	2018-08-28
US7959566	No	2011-06-14	2020-10-23
US8204763	No	2012-06-19	2018-08-28
US8315886	No	2012-11-20	2020-10-23
US8626531	No	2014-01-07	2020-10-23
US8589188	No	2013-11-19	2018-08-28
US7230012	No	2007-06-12	2023-12-09

Properties

State

Solid

Experimental Properties

Property	Value	Source
melting point (°C)	270 °C	PhysProp
water solubility	545 mg/L (at 25 °C)	BUDAVARI,S ET AL. (1996)
logP	0.33	HANSCH,C ET AL. (1995)

Predicted Properties

Property	Value	Source
Water Solubility	2.55 mg/mL	ALOGPS
logP	0.42	ALOGPS
logP	0.016	Chemaxon
logS	-2	ALOGPS
pKa (Strongest Acidic)	11.59	Chemaxon
pKa (Strongest Basic)	-6.4	Chemaxon
Physiological Charge	0	Chemaxon
Hydrogen Acceptor Count	4	Chemaxon
Hydrogen Donor Count	1	Chemaxon
Polar Surface Area	83.55 Å²	Chemaxon
Rotatable Bond Count	1	Chemaxon
Refractivity	64.32 m³·mol^-1	Chemaxon
Polarizability	24.42 Å³	Chemaxon
Number of Rings	3	Chemaxon
Bioavailability	1	Chemaxon
Rule of Five	Yes	Chemaxon
Ghose Filter	Yes	Chemaxon
Veber's Rule	No	Chemaxon
MDDR-like Rule	No	Chemaxon

Predicted ADMET Features

Property	Value	Probability
Human Intestinal Absorption	+	0.9775
Blood Brain Barrier	+	0.9382
Caco-2 permeable	-	0.5651
P-glycoprotein substrate	Substrate	0.5301
P-glycoprotein inhibitor I	Non-inhibitor	0.5115
P-glycoprotein inhibitor II	Non-inhibitor	0.8951
Renal organic cation transporter	Non-inhibitor	0.8179
CYP450 2C9 substrate	Non-substrate	0.7904
CYP450 2D6 substrate	Non-substrate	0.9116
CYP450 3A4 substrate	Substrate	0.5309
CYP450 1A2 substrate	Non-inhibitor	0.9045
CYP450 2C9 inhibitor	Non-inhibitor	0.9071
CYP450 2D6 inhibitor	Non-inhibitor	0.9231
CYP450 2C19 inhibitor	Non-inhibitor	0.9025
CYP450 3A4 inhibitor	Non-inhibitor	0.8309
CYP450 inhibitory promiscuity	Low CYP Inhibitory Promiscuity	0.8682
Ames test	Non AMES toxic	0.9133
Carcinogenicity	Non-carcinogens	0.9378
Biodegradation	Not ready biodegradable	0.8838
Rat acute toxicity	3.3039 LD50, mol/kg	Not applicable
hERG inhibition (predictor I)	Weak inhibitor	0.9769
hERG inhibition (predictor II)	Non-inhibitor	0.8735

ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted GC-MS Spectrum - GC-MS	Predicted GC-MS	splash10-05d0-4950000000-f29254c7cc48a749c100
Mass Spectrum (Electron Ionization)	MS	splash10-0wba-4900000000-77362eaf27267f59650d
LC-MS/MS Spectrum - LC-ESI-qTof , Positive	LC-MS/MS	splash10-000i-1940000000-f6d6997d1eaa7a83ec1b
LC-MS/MS Spectrum - LC-ESI-qTof , Positive	LC-MS/MS	splash10-000i-0930000000-e92e8e23d5db87f50f53
LC-MS/MS Spectrum - LC-ESI-qTof , Positive	LC-MS/MS	splash10-0019-2900000000-ecfd1b7ec17b857ea977
MS/MS Spectrum - , positive	LC-MS/MS	splash10-000i-0930000000-e92e8e23d5db87f50f53
MS/MS Spectrum - , positive	LC-MS/MS	splash10-000i-1940000000-f6d6997d1eaa7a83ec1b
MS/MS Spectrum - , positive	LC-MS/MS	splash10-0019-2900000000-ecfd1b7ec17b857ea977
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0002-0930000000-13e39078e3b7c3388463
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	splash10-052b-0980000000-2662087743922855f299
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0a4i-0890000000-30fe4d2107f121bf1159
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	splash10-0a4j-1690000000-6a9c01d748fa98f0d01f
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0a4i-3900000000-16bb9466e9660deaed65
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	splash10-0006-8910000000-cf577995bbea1990daf0
Predicted 1H NMR Spectrum	1D NMR	Not Applicable
Predicted 13C NMR Spectrum	1D NMR	Not Applicable

Chromatographic Properties

Collision Cross Sections (CCS)

Adduct	CCS Value (Å²)	Source type	Source
[M-H]-	164.9630183	predicted	DarkChem Lite v0.1.0
[M-H]-	153.08026	predicted	DeepCCS 1.0 (2019)
[M+H]+	165.3674183	predicted	DarkChem Lite v0.1.0
[M+H]+	155.46243	predicted	DeepCCS 1.0 (2019)
[M+Na]+	165.2130183	predicted	DarkChem Lite v0.1.0
[M+Na]+	161.5314	predicted	DeepCCS 1.0 (2019)

Targets

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insights and accelerate drug research.

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Details1. Tumor necrosis factor

Kind: Protein
Organism: Humans
Pharmacological action: Yes
Actions: Inhibitor

General Function: Cytokine that binds to TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR. It is mainly secreted by macrophages and can induce cell death of certain tumor cell lines. It is potent pyrogen causing fever by direct action or by stimulation of interleukin-1 secretion and is implicated in the induction of cachexia, Under certain conditions it can stimulate cell proliferation and induce cell differentiation. Impairs regulatory T-cells (Treg) function in individuals with rheumatoid arthritis via FOXP3 dephosphorylation. Up-regulates the expression of protein phosphatase 1 (PP1), which dephosphorylates the key 'Ser-418' residue of FOXP3, thereby inactivating FOXP3 and rendering Treg cells functionally defective (PubMed:23396208). Key mediator of cell death in the anticancer action of BCG-stimulated neutrophils in combination with DIABLO/SMAC mimetic in the RT4v6 bladder cancer cell line (PubMed:16829952, PubMed:22517918, PubMed:23396208). Induces insulin resistance in adipocytes via inhibition of insulin-induced IRS1 tyrosine phosphorylation and insulin-induced glucose uptake. Induces GKAP42 protein degradation in adipocytes which is partially responsible for TNF-induced insulin resistance (By similarity). Plays a role in angiogenesis by inducing VEGF production synergistically with IL1B and IL6 (PubMed:12794819). Promotes osteoclastogenesis and therefore mediates bone resorption (By similarity).
Specific Function: cytokine activity
Gene Name: TNF
Uniprot ID: P01375
Uniprot Name: Tumor necrosis factor
Molecular Weight: 25644.15 Da

References

Zhou Y, Zhang Y, Zhao D, Yu X, Shen X, Zhou Y, Wang S, Qiu Y, Chen Y, Zhu F: TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024 Jan 5;52(D1):D1465-D1477. doi: 10.1093/nar/gkad751. [Article]

Details2. Protein cereblon

Kind: Protein
Organism: Humans
Pharmacological action: Yes
Actions: Inhibitor

General Function: Substrate recognition component of a DCX (DDB1-CUL4-X-box) E3 protein ligase complex that mediates the ubiquitination and subsequent proteasomal degradation of target proteins, such as MEIS2 or ILF2 (PubMed:33009960). Normal degradation of key regulatory proteins is required for normal limb outgrowth and expression of the fibroblast growth factor FGF8 (PubMed:20223979, PubMed:24328678, PubMed:25043012, PubMed:25108355). Maintains presynaptic glutamate release and consequently cognitive functions, such as memory and learning, by negatively regulating large-conductance calcium-activated potassium (BK) channels in excitatory neurons (PubMed:18414909, PubMed:29530986). Likely to function by regulating the assembly and neuronal surface expression of BK channels via its interaction with KCNT1 (PubMed:18414909). May also be involved in regulating anxiety-like behaviors via a BK channel-independent mechanism (By similarity). Plays a negative role in TLR4 signaling by interacting with TRAF6 and ECSIT, leading to inhibition of ECSIT ubiquitination, an important step of the signaling (PubMed:31620128).
Specific Function: metal ion binding
Gene Name: CRBN
Uniprot ID: Q96SW2
Uniprot Name: Protein cereblon
Molecular Weight: 50545.375 Da

References

Zhu YX, Kortuem KM, Stewart AK: Molecular mechanism of action of immune-modulatory drugs thalidomide, lenalidomide and pomalidomide in multiple myeloma. Leuk Lymphoma. 2013 Apr;54(4):683-7. doi: 10.3109/10428194.2012.728597. Epub 2012 Sep 28. [Article]

Details3. DNA

Kind

Nucleotide

Organism

Humans

Pharmacological action

Yes

Actions

Intercalation

DNA is the molecule of heredity, as it is responsible for the genetic propagation of most inherited traits. It is a polynucleic acid that carries genetic information on cell growth, division, and function. DNA consists of two long strands of nucleotides twisted into a double helix and held together by hydrogen bonds. The sequence of nucleotides determines hereditary characteristics. Each strand serves as the template for subsequent DNA replication and as a template for mRNA production, leading to protein synthesis via ribosomes.

References

Stephens TD, Bunde CJ, Fillmore BJ: Mechanism of action in thalidomide teratogenesis. Biochem Pharmacol. 2000 Jun 15;59(12):1489-99. [Article]
Shoji A, Kuwahara M, Ozaki H, Sawai H: Modified DNA aptamer that binds the (R)-isomer of a thalidomide derivative with high enantioselectivity. J Am Chem Soc. 2007 Feb 7;129(5):1456-64. [Article]
Stephens TD, Fillmore BJ: Hypothesis: thalidomide embryopathy-proposed mechanism of action. Teratology. 2000 Mar;61(3):189-95. [Article]
Koch HP, Czejka MJ: Evidence for the intercalation of thalidomide into DNA: clue to the molecular mechanism of thalidomide teratogenicity? Z Naturforsch C J Biosci. 1986 Nov-Dec;41(11-12):1057-61. [Article]

Details4. alpha1-acid glycoprotein (Protein Group)

Kind: Protein group
Organism: Humans
Pharmacological action: Yes
Actions: Binder

General Function: Functions as a transport protein in the blood stream. Binds various ligands in the interior of its beta-barrel domain. Also binds synthetic drugs and influences their distribution and availability in the body. Appears to function in modulating the activity of the immune system during the acute-phase reaction.
Specific Function: Not Available

Components:

Name	UniProt ID
Alpha-1-acid glycoprotein 1	P02763
Alpha-1-acid glycoprotein 2	P19652

References

Turk BE, Jiang H, Liu JO: Binding of thalidomide to alpha1-acid glycoprotein may be involved in its inhibition of tumor necrosis factor alpha production. Proc Natl Acad Sci U S A. 1996 Jul 23;93(15):7552-6. [Article]

Enzymes

Details1. Cytochrome P450 1A1

Kind: Protein
Organism: Humans
Pharmacological action: No
Actions: Substrate

General Function: A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids, steroid hormones and vitamins (PubMed:10681376, PubMed:11555828, PubMed:12865317, PubMed:14559847, PubMed:15041462, PubMed:15805301, PubMed:18577768, PubMed:19965576, PubMed:20972997). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:10681376, PubMed:11555828, PubMed:12865317, PubMed:14559847, PubMed:15041462, PubMed:15805301, PubMed:18577768, PubMed:19965576, PubMed:20972997). Catalyzes the hydroxylation of carbon-hydrogen bonds. Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2, as well as D-ring hydroxylated E1 and E2 at the C15-alpha and C16-alpha positions (PubMed:11555828, PubMed:12865317, PubMed:14559847, PubMed:15805301). Displays different regioselectivities for polyunsaturated fatty acids (PUFA) hydroxylation (PubMed:15041462, PubMed:18577768). Catalyzes the epoxidation of double bonds of certain PUFA (PubMed:15041462, PubMed:19965576, PubMed:20972997). Converts arachidonic acid toward epoxyeicosatrienoic acid (EET) regioisomers, 8,9-, 11,12-, and 14,15-EET, that function as lipid mediators in the vascular system (PubMed:20972997). Displays an absolute stereoselectivity in the epoxidation of eicosapentaenoic acid (EPA) producing the 17(R),18(S) enantiomer (PubMed:15041462). May play an important role in all-trans retinoic acid biosynthesis in extrahepatic tissues. Catalyzes two successive oxidative transformation of all-trans retinol to all-trans retinal and then to the active form all-trans retinoic acid (PubMed:10681376). May also participate in eicosanoids metabolism by converting hydroperoxide species into oxo metabolites (lipoxygenase-like reaction, NADPH-independent) (PubMed:21068195).
Specific Function: arachidonic acid monooxygenase activity
Gene Name: CYP1A1
Uniprot ID: P04798
Uniprot Name: Cytochrome P450 1A1
Molecular Weight: 58164.815 Da

References

Ando Y, Fuse E, Figg WD: Thalidomide metabolism by the CYP2C subfamily. Clin Cancer Res. 2002 Jun;8(6):1964-73. [Article]

Details2. Cytochrome P450 2B6

Kind: Protein
Organism: Humans
Pharmacological action: No
Actions: Substrate
Inducer

General Function: A cytochrome P450 monooxygenase involved in the metabolism of endocannabinoids and steroids (PubMed:12865317, PubMed:21289075). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the epoxidation of double bonds of arachidonoylethanolamide (anandamide) to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:21289075). Hydroxylates steroid hormones, including testosterone at C-16 and estrogens at C-2 (PubMed:12865317, PubMed:21289075). Plays a role in the oxidative metabolism of xenobiotics, including plant lipids and drugs (PubMed:11695850, PubMed:22909231). Acts as a 1,4-cineole 2-exo-monooxygenase (PubMed:11695850).
Specific Function: anandamide 11,12 epoxidase activity
Gene Name: CYP2B6
Uniprot ID: P20813
Uniprot Name: Cytochrome P450 2B6
Molecular Weight: 56277.81 Da

References

Ando Y, Fuse E, Figg WD: Thalidomide metabolism by the CYP2C subfamily. Clin Cancer Res. 2002 Jun;8(6):1964-73. [Article]
Murayama N, van Beuningen R, Suemizu H, Guillouzo CG, Shibata N, Yajima K, Utoh M, Shimizu M, Chesne C, Nakamura M, Guengerich FP, Houtman R, Yamazaki H: Thalidomide increases human hepatic cytochrome P450 3A enzymes by direct activation of the pregnane X receptor. Chem Res Toxicol. 2014 Feb 17;27(2):304-308. doi: 10.1021/tx4004374. Epub 2014 Feb 5. [Article]
Deeken JF, Cormier T, Price DK, Sissung TM, Steinberg SM, Tran K, Liewehr DJ, Dahut WL, Miao X, Figg WD: A pharmacogenetic study of docetaxel and thalidomide in patients with castration-resistant prostate cancer using the DMET genotyping platform. Pharmacogenomics J. 2010 Jun;10(3):191-9. doi: 10.1038/tpj.2009.57. Epub 2009 Dec 29. [Article]

Details3. Cytochrome P450 2C9

Kind: Protein
Organism: Humans
Pharmacological action: No
Actions: Substrate

General Function: A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids and steroids (PubMed:12865317, PubMed:15766564, PubMed:19965576, PubMed:21576599, PubMed:7574697, PubMed:9435160, PubMed:9866708). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:12865317, PubMed:15766564, PubMed:19965576, PubMed:21576599, PubMed:7574697, PubMed:9435160, PubMed:9866708). Catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) (PubMed:15766564, PubMed:19965576, PubMed:7574697, PubMed:9866708). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes cholesterol toward 25-hydroxycholesterol, a physiological regulator of cellular cholesterol homeostasis (PubMed:21576599). Exhibits low catalytic activity for the formation of catechol estrogens from 17beta-estradiol (E2) and estrone (E1), namely 2-hydroxy E1 and E2 (PubMed:12865317). Catalyzes bisallylic hydroxylation and hydroxylation with double-bond migration of polyunsaturated fatty acids (PUFA) (PubMed:9435160, PubMed:9866708). Also metabolizes plant monoterpenes such as limonene. Oxygenates (R)- and (S)-limonene to produce carveol and perillyl alcohol (PubMed:11950794). Contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S-warfarin, diclofenac, phenytoin, tolbutamide and losartan (PubMed:25994031).
Specific Function: (R)-limonene 6-monooxygenase activity
Gene Name: CYP2C9
Uniprot ID: P11712
Uniprot Name: Cytochrome P450 2C9
Molecular Weight: 55627.365 Da

References

Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. [Article]
Ando Y, Fuse E, Figg WD: Thalidomide metabolism by the CYP2C subfamily. Clin Cancer Res. 2002 Jun;8(6):1964-73. [Article]

Details4. Cytochrome P450 3A4

Kind: Protein
Organism: Humans
Pharmacological action: No
Actions: Substrate
Inducer

General Function: A cytochrome P450 monooxygenase involved in the metabolism of sterols, steroid hormones, retinoids and fatty acids (PubMed:10681376, PubMed:11093772, PubMed:11555828, PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:19965576, PubMed:20702771, PubMed:21490593, PubMed:21576599). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:21490593, PubMed:21576599, PubMed:2732228). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2, as well as D-ring hydroxylated E1 and E2 at the C-16 position (PubMed:11555828, PubMed:12865317, PubMed:14559847). Plays a role in the metabolism of androgens, particularly in oxidative deactivation of testosterone (PubMed:15373842, PubMed:15764715, PubMed:22773874, PubMed:2732228). Metabolizes testosterone to less biologically active 2beta- and 6beta-hydroxytestosterones (PubMed:15373842, PubMed:15764715, PubMed:2732228). Contributes to the formation of hydroxycholesterols (oxysterols), particularly A-ring hydroxylated cholesterol at the C-4beta position, and side chain hydroxylated cholesterol at the C-25 position, likely contributing to cholesterol degradation and bile acid biosynthesis (PubMed:21576599). Catalyzes bisallylic hydroxylation of polyunsaturated fatty acids (PUFA) (PubMed:9435160). Catalyzes the epoxidation of double bonds of PUFA with a preference for the last double bond (PubMed:19965576). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:20702771). Plays a role in the metabolism of retinoids. Displays high catalytic activity for oxidation of all-trans-retinol to all-trans-retinal, a rate-limiting step for the biosynthesis of all-trans-retinoic acid (atRA) (PubMed:10681376). Further metabolizes atRA toward 4-hydroxyretinoate and may play a role in hepatic atRA clearance (PubMed:11093772). Responsible for oxidative metabolism of xenobiotics. Acts as a 2-exo-monooxygenase for plant lipid 1,8-cineole (eucalyptol) (PubMed:11159812). Metabolizes the majority of the administered drugs. Catalyzes sulfoxidation of the anthelmintics albendazole and fenbendazole (PubMed:10759686). Hydroxylates antimalarial drug quinine (PubMed:8968357). Acts as a 1,4-cineole 2-exo-monooxygenase (PubMed:11695850). Also involved in vitamin D catabolism and calcium homeostasis. Catalyzes the inactivation of the active hormone calcitriol (1-alpha,25-dihydroxyvitamin D(3)) (PubMed:29461981).
Specific Function: 1,8-cineole 2-exo-monooxygenase activity
Gene Name: CYP3A4
Uniprot ID: P08684
Uniprot Name: Cytochrome P450 3A4
Molecular Weight: 57342.67 Da

References

Murayama N, van Beuningen R, Suemizu H, Guillouzo CG, Shibata N, Yajima K, Utoh M, Shimizu M, Chesne C, Nakamura M, Guengerich FP, Houtman R, Yamazaki H: Thalidomide increases human hepatic cytochrome P450 3A enzymes by direct activation of the pregnane X receptor. Chem Res Toxicol. 2014 Feb 17;27(2):304-308. doi: 10.1021/tx4004374. Epub 2014 Feb 5. [Article]
Chowdhury G, Murayama N, Okada Y, Uno Y, Shimizu M, Shibata N, Guengerich FP, Yamazaki H: Human liver microsomal cytochrome P450 3A enzymes involved in thalidomide 5-hydroxylation and formation of a glutathione conjugate. Chem Res Toxicol. 2010 Jun 21;23(6):1018-24. doi: 10.1021/tx900367p. [Article]

Details5. Cytochrome P450 2C19

Kind: Protein
Organism: Humans
Pharmacological action: No
Actions: Substrate
Inhibitor

General Function: A cytochrome P450 monooxygenase involved in the metabolism of polyunsaturated fatty acids (PUFA) (PubMed:18577768, PubMed:19965576, PubMed:20972997). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:18577768, PubMed:19965576, PubMed:20972997). Catalyzes the hydroxylation of carbon-hydrogen bonds. Hydroxylates PUFA specifically at the omega-1 position (PubMed:18577768). Catalyzes the epoxidation of double bonds of PUFA (PubMed:19965576, PubMed:20972997). Also metabolizes plant monoterpenes such as limonene. Oxygenates (R)- and (S)-limonene to produce carveol and perillyl alcohol (PubMed:11950794). Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and imipramine. Hydroxylates fenbendazole at the 4' position (PubMed:23959307).
Specific Function: (R)-limonene 6-monooxygenase activity
Gene Name: CYP2C19
Uniprot ID: P33261
Uniprot Name: Cytochrome P450 2C19
Molecular Weight: 55944.565 Da

References

Okada Y, Murayama N, Yanagida C, Shimizu M, Guengerich FP, Yamazaki H: Drug interactions of thalidomide with midazolam and cyclosporine A: heterotropic cooperativity of human cytochrome P450 3A5. Drug Metab Dispos. 2009 Jan;37(1):18-23. doi: 10.1124/dmd.108.024679. Epub 2008 Oct 23. [Article]
Ando Y, Fuse E, Figg WD: Thalidomide metabolism by the CYP2C subfamily. Clin Cancer Res. 2002 Jun;8(6):1964-73. [Article]
Li Y, Jiang Z, Xiao Y, Li L, Gao Y: Metabolism of thalidomide by human liver microsome cytochrome CYP2C19 is required for its antimyeloma and antiangiogenic activities in vitro. Hematol Oncol. 2012 Mar;30(1):13-21. doi: 10.1002/hon.992. Epub 2011 Jun 3. [Article]
Ando Y, Price DK, Dahut WL, Cox MC, Reed E, Figg WD: Pharmacogenetic associations of CYP2C19 genotype with in vivo metabolisms and pharmacological effects of thalidomide. Cancer Biol Ther. 2002 Nov-Dec;1(6):669-73. doi: 10.4161/cbt.318. [Article]

Details6. Cytochrome P450 3A5

Kind: Protein
Organism: Humans
Pharmacological action: No
Actions: Substrate
Inducer

General Function: A cytochrome P450 monooxygenase involved in the metabolism of steroid hormones and vitamins (PubMed:10681376, PubMed:11093772, PubMed:12865317, PubMed:2732228). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:10681376, PubMed:11093772, PubMed:12865317, PubMed:2732228). Exhibits high catalytic activity for the formation of catechol estrogens from 17beta-estradiol (E2) and estrone (E1), namely 2-hydroxy E1 and E2 (PubMed:12865317). Catalyzes 6beta-hydroxylation of the steroid hormones testosterone, progesterone, and androstenedione (PubMed:2732228). Catalyzes the oxidative conversion of all-trans-retinol to all-trans-retinal, a rate-limiting step for the biosynthesis of all-trans-retinoic acid (atRA) (PubMed:10681376). Further metabolizes all trans-retinoic acid (atRA) to 4-hydroxyretinoate and may play a role in hepatic atRA clearance (PubMed:11093772). Also involved in the oxidative metabolism of xenobiotics, including calcium channel blocking drug nifedipine and immunosuppressive drug cyclosporine (PubMed:2732228).
Specific Function: aromatase activity
Gene Name: CYP3A5
Uniprot ID: P20815
Uniprot Name: Cytochrome P450 3A5
Molecular Weight: 57108.065 Da

References

Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. [Article]
Chowdhury G, Murayama N, Okada Y, Uno Y, Shimizu M, Shibata N, Guengerich FP, Yamazaki H: Human liver microsomal cytochrome P450 3A enzymes involved in thalidomide 5-hydroxylation and formation of a glutathione conjugate. Chem Res Toxicol. 2010 Jun 21;23(6):1018-24. doi: 10.1021/tx900367p. [Article]

Details7. Prostaglandin G/H synthase 1

Kind: Protein
Organism: Humans
Pharmacological action: No
Actions: Substrate

General Function: Dual cyclooxygenase and peroxidase that plays an important role in the biosynthesis pathway of prostanoids, a class of C20 oxylipins mainly derived from arachidonate ((5Z,8Z,11Z,14Z)-eicosatetraenoate, AA, C20:4(n-6)), with a particular role in the inflammatory response. The cyclooxygenase activity oxygenates AA to the hydroperoxy endoperoxide prostaglandin G2 (PGG2), and the peroxidase activity reduces PGG2 to the hydroxy endoperoxide prostaglandin H2 (PGH2), the precursor of all 2-series prostaglandins and thromboxanes. This complex transformation is initiated by abstraction of hydrogen at carbon 13 (with S-stereochemistry), followed by insertion of molecular O2 to form the endoperoxide bridge between carbon 9 and 11 that defines prostaglandins. The insertion of a second molecule of O2 (bis-oxygenase activity) yields a hydroperoxy group in PGG2 that is then reduced to PGH2 by two electrons (PubMed:7947975). Involved in the constitutive production of prostanoids in particular in the stomach and platelets. In gastric epithelial cells, it is a key step in the generation of prostaglandins, such as prostaglandin E2 (PGE2), which plays an important role in cytoprotection. In platelets, it is involved in the generation of thromboxane A2 (TXA2), which promotes platelet activation and aggregation, vasoconstriction and proliferation of vascular smooth muscle cells (Probable). Can also use linoleate (LA, (9Z,12Z)-octadecadienoate, C18:2(n-6)) as substrate and produce hydroxyoctadecadienoates (HODEs) in a regio- and stereospecific manner, being (9R)-HODE ((9R)-hydroxy-(10E,12Z)-octadecadienoate) and (13S)-HODE ((13S)-hydroxy-(9Z,11E)-octadecadienoate) its major products (By similarity).
Specific Function: heme binding
Gene Name: PTGS1
Uniprot ID: P23219
Uniprot Name: Prostaglandin G/H synthase 1
Molecular Weight: 68685.82 Da

References

Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. [Article]

Details8. Prostaglandin G/H synthase 2

Kind: Protein
Organism: Humans
Pharmacological action: No
Actions: Substrate

General Function: Dual cyclooxygenase and peroxidase in the biosynthesis pathway of prostanoids, a class of C20 oxylipins mainly derived from arachidonate ((5Z,8Z,11Z,14Z)-eicosatetraenoate, AA, C20:4(n-6)), with a particular role in the inflammatory response (PubMed:11939906, PubMed:16373578, PubMed:19540099, PubMed:22942274, PubMed:26859324, PubMed:27226593, PubMed:7592599, PubMed:7947975, PubMed:9261177). The cyclooxygenase activity oxygenates AA to the hydroperoxy endoperoxide prostaglandin G2 (PGG2), and the peroxidase activity reduces PGG2 to the hydroxy endoperoxide prostaglandin H2 (PGH2), the precursor of all 2-series prostaglandins and thromboxanes (PubMed:16373578, PubMed:22942274, PubMed:26859324, PubMed:27226593, PubMed:7592599, PubMed:7947975, PubMed:9261177). This complex transformation is initiated by abstraction of hydrogen at carbon 13 (with S-stereochemistry), followed by insertion of molecular O2 to form the endoperoxide bridge between carbon 9 and 11 that defines prostaglandins. The insertion of a second molecule of O2 (bis-oxygenase activity) yields a hydroperoxy group in PGG2 that is then reduced to PGH2 by two electrons (PubMed:16373578, PubMed:22942274, PubMed:26859324, PubMed:27226593, PubMed:7592599, PubMed:7947975, PubMed:9261177). Similarly catalyzes successive cyclooxygenation and peroxidation of dihomo-gamma-linoleate (DGLA, C20:3(n-6)) and eicosapentaenoate (EPA, C20:5(n-3)) to corresponding PGH1 and PGH3, the precursors of 1- and 3-series prostaglandins (PubMed:11939906, PubMed:19540099). In an alternative pathway of prostanoid biosynthesis, converts 2-arachidonoyl lysophopholipids to prostanoid lysophopholipids, which are then hydrolyzed by intracellular phospholipases to release free prostanoids (PubMed:27642067). Metabolizes 2-arachidonoyl glycerol yielding the glyceryl ester of PGH2, a process that can contribute to pain response (PubMed:22942274). Generates lipid mediators from n-3 and n-6 polyunsaturated fatty acids (PUFAs) via a lipoxygenase-type mechanism. Oxygenates PUFAs to hydroperoxy compounds and then reduces them to corresponding alcohols (PubMed:11034610, PubMed:11192938, PubMed:9048568, PubMed:9261177). Plays a role in the generation of resolution phase interaction products (resolvins) during both sterile and infectious inflammation (PubMed:12391014). Metabolizes docosahexaenoate (DHA, C22:6(n-3)) to 17R-HDHA, a precursor of the D-series resolvins (RvDs) (PubMed:12391014). As a component of the biosynthetic pathway of E-series resolvins (RvEs), converts eicosapentaenoate (EPA, C20:5(n-3)) primarily to 18S-HEPE that is further metabolized by ALOX5 and LTA4H to generate 18S-RvE1 and 18S-RvE2 (PubMed:21206090). In vascular endothelial cells, converts docosapentaenoate (DPA, C22:5(n-3)) to 13R-HDPA, a precursor for 13-series resolvins (RvTs) shown to activate macrophage phagocytosis during bacterial infection (PubMed:26236990). In activated leukocytes, contributes to oxygenation of hydroxyeicosatetraenoates (HETE) to diHETES (5,15-diHETE and 5,11-diHETE) (PubMed:22068350, PubMed:26282205). Can also use linoleate (LA, (9Z,12Z)-octadecadienoate, C18:2(n-6)) as substrate and produce hydroxyoctadecadienoates (HODEs) in a regio- and stereospecific manner, being (9R)-HODE ((9R)-hydroxy-(10E,12Z)-octadecadienoate) and (13S)-HODE ((13S)-hydroxy-(9Z,11E)-octadecadienoate) its major products (By similarity). During neuroinflammation, plays a role in neuronal secretion of specialized preresolving mediators (SPMs) 15R-lipoxin A4 that regulates phagocytic microglia (By similarity).
Specific Function: enzyme binding
Gene Name: PTGS2
Uniprot ID: P35354
Uniprot Name: Prostaglandin G/H synthase 2
Molecular Weight: 68995.625 Da

References

Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. [Article]

Drug created at June 13, 2005 13:24 / Updated at August 26, 2024 19:23

Thalidomide

Identification

Structure for Thalidomide (DB01041)

Pharmacology

Interactions

Products

Categories

Chemical Identifiers

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Clinical Trials

Clinical Trial & Rare Diseases Add-on Data Package

Pharmacoeconomics

Properties

Spectra

Collision Cross Sections (CCS)

Targets

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Components:

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Enzymes

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