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Record Information
Version3.6
Creation Date2012-09-06 15:16:51 UTC
Update Date2016-02-11 01:32:18 UTC
HMDB IDHMDB15300
Secondary Accession NumbersNone
Metabolite Identification
Common NameArsenic trioxide
DescriptionArsenic trioxide is a chemotheraputic agent of idiopathic function used to treat leukemia that is unresponsive to first line agents. It is suspected that arsenic trisulfide induces cancer cells to undergo apoptosis. Due to the toxic nature of arsenic, this drug carries significant health risks. The enzyme thioredoxin reductase has recently been identified as a target for arsenic trioxide.
Structure
Thumb
Synonyms
ValueSource
Arseni trioxydumHMDB
Arsenic oxidearsenous trioxideHMDB
Arsenious acidHMDB
Arsenious trioxideHMDB
ArsentrioxideHMDB
Chemical FormulaAs2O3
Average Molecular Weight197.8414
Monoisotopic Molecular Weight197.8279367
IUPAC Namebicyclo[1.1.1]diarsoxane
Traditional Namearsenic trioxide
CAS Registry Number1327-53-3
SMILES
O1[As]2O[As]1O2
InChI Identifier
InChI=1S/As2O3/c3-1-4-2(3)5-1
InChI KeyInChIKey=GOLCXWYRSKYTSP-UHFFFAOYSA-N
Chemical Taxonomy
DescriptionThis compound belongs to the class of inorganic compounds known as miscellaneous arsenites. These are inorganic compounds in which the largest metallic oxoanion is arsenite, to which either no atom or a non metal atom is bonded.
KingdomInorganic compounds
Super ClassMixed metal/non-metal compounds
ClassMiscellaneous mixed metal/non-metals
Sub ClassMiscellaneous metallic oxoanionic compounds
Direct ParentMiscellaneous arsenites
Alternative Parents
Substituents
  • Arsenite
  • Trivalent inorganic arsenic compound
  • Oxacycle
  • Inorganic metalloid salt
  • Inorganic arsenic compound
  • Heteropolycyclic compound
Molecular FrameworkHeteropolycyclic compounds
External DescriptorsNot Available
Ontology
StatusExpected but not Quantified
Origin
  • Drug
Biofunction
  • Antineoplastic Agents
  • Homeopathic Agents
Application
  • Pharmaceutical
Cellular locations
  • Cytoplasm
  • Membrane
Physical Properties
StateSolid
Experimental Properties
PropertyValueReference
Melting PointNot AvailableNot Available
Boiling PointNot AvailableNot Available
Water SolubilityNot AvailableNot Available
LogPNot AvailableNot Available
Predicted Properties
PropertyValueSource
logP2.31ChemAxon
pKa (Strongest Basic)-5.2ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area27.69 Å2ChemAxon
Rotatable Bond Count0ChemAxon
Refractivity4.05 m3·mol-1ChemAxon
Polarizability7.14 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash Key
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, NegativeNot Available
Biological Properties
Cellular Locations
  • Cytoplasm
  • Membrane
Biofluid Locations
  • Blood
  • Urine
Tissue LocationNot Available
PathwaysNot Available
Normal Concentrations
BiofluidStatusValueAgeSexConditionReferenceDetails
BloodExpected but not QuantifiedNot ApplicableNot AvailableNot AvailableTaking drug identified by DrugBank entry DB01169
  • Not Applicable
details
UrineExpected but not QuantifiedNot ApplicableNot AvailableNot AvailableTaking drug identified by DrugBank entry DB01169
  • Not Applicable
details
Abnormal Concentrations
Not Available
Associated Disorders and Diseases
Disease ReferencesNone
Associated OMIM IDsNone
DrugBank IDDB01169
DrugBank Metabolite IDNot Available
Phenol Explorer Compound IDNot Available
Phenol Explorer Metabolite IDNot Available
FoodDB IDNot Available
KNApSAcK IDNot Available
Chemspider ID452539
KEGG Compound IDNot Available
BioCyc IDNot Available
BiGG IDNot Available
Wikipedia LinkArsenic_trioxide
NuGOwiki LinkHMDB15300
Metagene LinkHMDB15300
METLIN IDNot Available
PubChem Compound518740
PDB IDNot Available
ChEBI IDNot Available
References
Synthesis ReferenceNot Available
Material Safety Data Sheet (MSDS)Download (PDF)
General References
  1. Lu J, Chew EH, Holmgren A: Targeting thioredoxin reductase is a basis for cancer therapy by arsenic trioxide. Proc Natl Acad Sci U S A. 2007 Jul 24;104(30):12288-93. Epub 2007 Jul 18. [17640917 ]

Enzymes

General function:
Involved in oxidoreductase activity
Specific function:
Isoform 1 may possess glutaredoxin activity as well as thioredoxin reductase activity and induces actin and tubulin polymerization, leading to formation of cell membrane protrusions. Isoform 4 enhances the transcriptional activity of estrogen receptors alpha and beta while isoform 5 enhances the transcriptional activity of the beta receptor only. Isoform 5 also mediates cell death induced by a combination of interferon-beta and retinoic acid.
Gene Name:
TXNRD1
Uniprot ID:
Q16881
Molecular weight:
70905.58
References
  1. Lu J, Chew EH, Holmgren A: Targeting thioredoxin reductase is a basis for cancer therapy by arsenic trioxide. Proc Natl Acad Sci U S A. 2007 Jul 24;104(30):12288-93. Epub 2007 Jul 18. [17640917 ]
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 performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Acts as a 1,8-cineole 2-exo-monooxygenase. The enzyme also hydroxylates etoposide.
Gene Name:
CYP3A4
Uniprot ID:
P08684
Molecular weight:
57255.585
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. Epub 2009 Nov 24. [19934256 ]
General function:
Involved in MAP kinase activity
Specific function:
Acts as a transcriptional repressor. Binds to a [GC]AAA[GC] consensus sequence. Repress the expression of interferon gamma-induced genes. Seems to bind to the promoter of CCL5, DMP1, IFIH1, IFITM1, IRF7, IRF9, LAMP3, OAS1, OAS2, OAS3 and STAT1. Transcriptional activity is independent of kinase activity
Gene Name:
MAPK1
Uniprot ID:
P28482
Molecular weight:
41389.3
References
  1. Dong Z: The molecular mechanisms of arsenic-induced cell transformation and apoptosis. Environ Health Perspect. 2002 Oct;110 Suppl 5:757-9. [12426127 ]
  2. He Z, Ma WY, Liu G, Zhang Y, Bode AM, Dong Z: Arsenite-induced phosphorylation of histone H3 at serine 10 is mediated by Akt1, extracellular signal-regulated kinase 2, and p90 ribosomal S6 kinase 2 but not J Biol Chem. 2003 Mar 21;278(12):10588-93. Epub 2003 Jan 14. [12529330 ]
General function:
Involved in MAP kinase activity
Specific function:
Involved in both the initiation and regulation of meiosis, mitosis, and postmitotic functions in differentiated cells by phosphorylating a number of transcription factors such as ELK-1. Phosphorylates EIF4EBP1; required for initiation of translation. Phosphorylates microtubule-associated protein 2 (MAP2). Phosphorylates SPZ1. Phosphorylates heat shock factor protein 4 (HSF4)
Gene Name:
MAPK3
Uniprot ID:
P27361
Molecular weight:
43135.2
References
  1. Fauconneau B, Petegnief V, Sanfeliu C, Piriou A, Planas AM: Induction of heat shock proteins (HSPs) by sodium arsenite in cultured astrocytes and reduction of hydrogen peroxide-induced cell death. J Neurochem. 2002 Dec;83(6):1338-48. [12472888 ]
  2. Jung DK, Bae GU, Kim YK, Han SH, Choi WS, Kang H, Seo DW, Lee HY, Cho EJ, Lee HW, Han JW: Hydrogen peroxide mediates arsenite activation of p70(s6k) and extracellular signal-regulated kinase. Exp Cell Res. 2003 Oct 15;290(1):144-54. [14516795 ]
  3. Tanaka-Kagawa T, Hanioka N, Yoshida H, Jinno H, Ando M: Arsenite and arsenate activate extracellular signal-regulated kinases 1/2 by an epidermal growth factor receptor-mediated pathway in normal human keratinocytes. Br J Dermatol. 2003 Dec;149(6):1116-27. [14674888 ]
  4. Felix K, Manna SK, Wise K, Barr J, Ramesh GT: Low levels of arsenite activates nuclear factor-kappaB and activator protein-1 in immortalized mesencephalic cells. J Biochem Mol Toxicol. 2005;19(2):67-77. [15849723 ]
  5. Mousa SA, O'Connor L, Rossman TG, Block E: Pro-angiogenesis action of arsenic and its reversal by selenium-derived compounds. Carcinogenesis. 2007 May;28(5):962-7. Epub 2006 Dec 8. [17158527 ]
General function:
Involved in protein kinase activity
Specific function:
Acts as part of the IKK complex in the conventional pathway of NF-kappa-B activation and phosphorylates inhibitors of NF-kappa-B thus leading to the dissociation of the inhibitor/NF- kappa-B complex and ultimately the degradation of the inhibitor. Also phosphorylates NCOA3
Gene Name:
IKBKB
Uniprot ID:
O14920
Molecular weight:
86563.2
References
  1. Ouyang W, Ma Q, Li J, Zhang D, Liu ZG, Rustgi AK, Huang C: Cyclin D1 induction through IkappaB kinase beta/nuclear factor-kappaB pathway is responsible for arsenite-induced increased cell cycle G1-S phase transition in human keratinocytes. Cancer Res. 2005 Oct 15;65(20):9287-93. [16230390 ]
  2. Ouyang W, Li J, Ma Q, Huang C: Essential roles of PI-3K/Akt/IKKbeta/NFkappaB pathway in cyclin D1 induction by arsenite in JB6 Cl41 cells. Carcinogenesis. 2006 Apr;27(4):864-73. Epub 2005 Dec 29. [16387740 ]
  3. Ouyang W, Zhang D, Ma Q, Li J, Huang C: Cyclooxygenase-2 induction by arsenite through the IKKbeta/NFkappaB pathway exerts an antiapoptotic effect in mouse epidermal Cl41 cells. Environ Health Perspect. 2007 Apr;115(4):513-8. Epub 2006 Dec 14. [17450217 ]
  4. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [11752352 ]
General function:
Involved in protein serine/threonine kinase activity
Specific function:
Plays a role as a key modulator of the AKT-mTOR signaling pathway controlling the tempo of the process of newborn neurons integration during adult neurogenesis, including correct neuron positioning, dendritic development and synapse formation. General protein kinase capable of phosphorylating several known proteins. Phosphorylates TBC1D4. Signals downstream of phosphatidylinositol 3-kinase (PI(3)K) to mediate the effects of various growth factors such as platelet-derived growth factor (PDGF), epidermal growth factor (EGF), insulin and insulin-like growth factor I (IGF-I). Plays a role in glucose transport by mediating insulin-induced translocation of the GLUT4 glucose transporter to the cell surface. Mediates the antiapoptotic effects of IGF-I. Mediates insulin-stimulated protein synthesis by phosphorylating TSC2 at 'Ser-939' and 'Thr-1462', thereby activating mTORC1 signaling and leading to both phosphorylation of 4E-BP1 and in activation of RPS6KB1. Promotes glycogen synthesis by mediating the insulin-induced activation of glycogen synthase
Gene Name:
AKT1
Uniprot ID:
P31749
Molecular weight:
55686.0
References
  1. Fauconneau B, Petegnief V, Sanfeliu C, Piriou A, Planas AM: Induction of heat shock proteins (HSPs) by sodium arsenite in cultured astrocytes and reduction of hydrogen peroxide-induced cell death. J Neurochem. 2002 Dec;83(6):1338-48. [12472888 ]
  2. He Z, Ma WY, Liu G, Zhang Y, Bode AM, Dong Z: Arsenite-induced phosphorylation of histone H3 at serine 10 is mediated by Akt1, extracellular signal-regulated kinase 2, and p90 ribosomal S6 kinase 2 but not J Biol Chem. 2003 Mar 21;278(12):10588-93. Epub 2003 Jan 14. [12529330 ]
  3. Ivanov VN, Hei TK: Combined treatment with EGFR inhibitors and arsenite upregulated apoptosis in human EGFR-positive melanomas: a role of suppression of the PI3K-AKT pathway. Oncogene. 2005 Jan 20;24(4):616-26. [15580309 ]
  4. Wang ZX, Jiang CS, Liu L, Wang XH, Jin HJ, Wu Q, Chen Q: The role of Akt on arsenic trioxide suppression of 3T3-L1 preadipocyte differentiation. Cell Res. 2005 May;15(5):379-86. [15916724 ]
  5. Tsou TC, Tsai FY, Hsieh YW, Li LA, Yeh SC, Chang LW: Arsenite induces endothelial cytotoxicity by down-regulation of vascular endothelial nitric oxide synthase. Toxicol Appl Pharmacol. 2005 Nov 1;208(3):277-84. [16239170 ]
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. Participates in the metabolism of an as-yet-unknown biologically active molecule that is a participant in eye development.
Gene Name:
CYP1B1
Uniprot ID:
Q16678
Molecular weight:
60845.33
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. Epub 2009 Nov 24. [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.
Gene Name:
CYP1A1
Uniprot ID:
P04798
Molecular weight:
58164.815
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. Epub 2009 Nov 24. [19934256 ]
General function:
Involved in sequence-specific DNA binding transcription factor activity
Specific function:
Transcription factor that recognizes and binds to the enhancer heptamer motif 5'-TGA[CG]TCA-3'
Gene Name:
JUN
Uniprot ID:
P05412
Molecular weight:
35675.3
References
  1. Muscarella DE, Bloom SE: Differential activation of the c-Jun N-terminal kinase pathway in arsenite-induced apoptosis and sensitization of chemically resistant compared to susceptible B-lymphoma cell lines. Toxicol Sci. 2002 Jul;68(1):82-92. [12075113 ]
  2. Dong Z: The molecular mechanisms of arsenic-induced cell transformation and apoptosis. Environ Health Perspect. 2002 Oct;110 Suppl 5:757-9. [12426127 ]
  3. Drobna Z, Jaspers I, Thomas DJ, Styblo M: Differential activation of AP-1 in human bladder epithelial cells by inorganic and methylated arsenicals. FASEB J. 2003 Jan;17(1):67-9. Epub 2002 Nov 15. [12475910 ]
  4. Li J, Gorospe M, Barnes J, Liu Y: Tumor promoter arsenite stimulates histone H3 phosphoacetylation of proto-oncogenes c-fos and c-jun chromatin in human diploid fibroblasts. J Biol Chem. 2003 Apr 11;278(15):13183-91. Epub 2003 Jan 23. [12547826 ]
  5. Kietzmann T, Samoylenko A, Immenschuh S: Transcriptional regulation of heme oxygenase-1 gene expression by MAP kinases of the JNK and p38 pathways in primary cultures of rat hepatocytes. J Biol Chem. 2003 May 16;278(20):17927-36. Epub 2003 Mar 11. [12637567 ]
General function:
Involved in protein kinase binding
Specific function:
Essential for the control of the cell cycle at the G1/S (start) transition
Gene Name:
CCND1
Uniprot ID:
P24385
Molecular weight:
33728.7
References
  1. Hyun Park W, Hee Cho Y, Won Jung C, Oh Park J, Kim K, Hyuck Im Y, Lee MH, Ki Kang W, Park K: Arsenic trioxide inhibits the growth of A498 renal cell carcinoma cells via cell cycle arrest or apoptosis. Biochem Biophys Res Commun. 2003 Jan 3;300(1):230-5. [12480548 ]
  2. Ouyang W, Ma Q, Li J, Zhang D, Liu ZG, Rustgi AK, Huang C: Cyclin D1 induction through IkappaB kinase beta/nuclear factor-kappaB pathway is responsible for arsenite-induced increased cell cycle G1-S phase transition in human keratinocytes. Cancer Res. 2005 Oct 15;65(20):9287-93. [16230390 ]
  3. Ouyang W, Li J, Ma Q, Huang C: Essential roles of PI-3K/Akt/IKKbeta/NFkappaB pathway in cyclin D1 induction by arsenite in JB6 Cl41 cells. Carcinogenesis. 2006 Apr;27(4):864-73. Epub 2005 Dec 29. [16387740 ]
  4. Hwang BJ, Utti C, Steinberg M: Induction of cyclin D1 by submicromolar concentrations of arsenite in human epidermal keratinocytes. Toxicol Appl Pharmacol. 2006 Dec 1;217(2):161-7. Epub 2006 Aug 11. [17005224 ]
  5. Ouyang W, Li J, Zhang D, Jiang BH, Huang DC: PI-3K/Akt signal pathway plays a crucial role in arsenite-induced cell proliferation of human keratinocytes through induction of cyclin D1. J Cell Biochem. 2007 Jul 1;101(4):969-78. [17370311 ]

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. Kauffmann HM, Pfannschmidt S, Zoller H, Benz A, Vorderstemann B, Webster JI, Schrenk D: Influence of redox-active compounds and PXR-activators on human MRP1 and MRP2 gene expression. Toxicology. 2002 Feb 28;171(2-3):137-46. [11836020 ]
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. Hu XM, Hirano T, Oka K: Arsenic trioxide induces apoptosis equally in T lymphoblastoid leukemia MOLT-4 cells and P-gp-expressing daunorubicin-resistant MOLT-4 cells. Cancer Chemother Pharmacol. 2003 Feb;51(2):119-26. Epub 2002 Nov 20. [12647012 ]
  2. Wei HL, Yao XJ, Li YN, Wang P, Zhao HS, Bai DC, Peng X, Ma LF: [Arsenic trioxide inhibits P-glycoprotein expression in multidrug-resistant human leukemia K562/ADM cell line that overexpresses mdr-1 gene and enhances their chemotherapeutic sensitivity]. Zhonghua Xue Ye Xue Za Zhi. 2003 Jan;24(1):28-31. [12679007 ]
  3. Wei H, Su H, Bai D, Zhao H, Ge J, Wang B, Yao X, Ma L: Arsenic trioxide inhibits p-glycoprotein expression in multidrug-resistant human leukemia cells that overexpress the MDR1 gene. Chin Med J (Engl). 2003 Nov;116(11):1644-8. [14642128 ]
  4. Kimura A, Ishida Y, Wada T, Yokoyama H, Mukaida N, Kondo T: MRP-1 expression levels determine strain-specific susceptibility to sodium arsenic-induced renal injury between C57BL/6 and BALB/c mice. Toxicol Appl Pharmacol. 2005 Feb 15;203(1):53-61. [15694464 ]
  5. Cronin CJ, Mendel JE, Mukhtar S, Kim YM, Stirbl RC, Bruck J, Sternberg PW: An automated system for measuring parameters of nematode sinusoidal movement. BMC Genet. 2005 Feb 7;6:5. [15698479 ]