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Showing toxin card for Methotrexate (T3D2486)

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Version 1.0
Creation Date 2009-07-03 22:10:49
Update Date 2010-05-18 20:57:22
Accession Number T3D2486
Name Methotrexate
Compound Type
  • Abortifacient Agent
  • Abortifacient Agent, Nonsteroidal
  • Antimetabolite
  • Antimetabolite, Antineoplastic
  • Antineoplastic Agent
  • Antirheumatic Agent
  • Dermatologic Agent
  • Drug
  • Enzyme Inhibitor
  • Folic Acid Antagonist
  • Immunosuppressive Agent
  • Nucleic Acid Synthesis Inhibitor
Description An antineoplastic antimetabolite with immunosuppressant properties. It is an inhibitor of tetrahydrofolate dehydrogenase and prevents the formation of tetrahydrofolate, necessary for synthesis of thymidylate, an essential component of DNA. [PubChem]
Synonyms
  1. (+)-amethopterin
  2. 1dhi
  3. 1dhj
  4. 2drc
  5. 4-Amino-10-methylfolic Acid
  6. 4-Amino-4-deoxy-N(sup10)-methylpteroylglutamic Acid
  7. 4-Amino-N(Sup10)-methylpteroylglutamic Acid
  8. 4-Amino-N(sup 10)-methylpteroylglutamic Acid
  9. 4-Amino-N10-methylpteroyl-L-glutamic Acid
  10. 4-Amino-N10-methylpteroylglutamic Acid
  11. 4-Aminomethylpteroylglutamic Acid
  12. 4-amino-N(10)-methylpteroylglutamic Acid
  13. A-methopterin
  14. A-methpterin
  15. Amethopterin
  16. Amethopterin l-
  17. Amethopterine
  18. Antifolan
  19. D-amethopterin
  20. Emtexate
  21. Folex
  22. Folex-PFS
  23. Hdmtx
  24. Intradose-MTX
  25. Intrathecal methotrexate
  26. Kyselina 4-amino-N(sup 10)-methylpteroylglutamova [Czech]
  27. Kyselina 4-amino-N10-methylpteroylglutamova
  28. Kyselina 4-desoxy-4-amino-N10-methyllistova
  29. L-amethopterin
  30. Ledertrexate
  31. MTX
  32. Maxtrex
  33. Metatrexan
  34. Methopterin
  35. Methotextrate
  36. Methotrexat
  37. Methotrexat-ebewe
  38. Methotrexate injection, usp
  39. Methotrexate preservative free
  40. Methotrexate sodium
  41. Methotrexate(usan)
  42. Methotrexate, l-
  43. Methotrexatum [inn-latin]
  44. Methylaminopterin
  45. Methylaminopterinum
  46. Metolate
  47. Metotressato [dcit]
  48. Metotrexato [inn-spanish]
  49. Mexate
  50. N-bismethylpteroylglutamic Acid
  51. Ratio-methotrexate sodium
  52. Rheumatrex
  53. Tocris-1230
  54. Trexall
Chemical IUPAC Name 2-[(4-{[(2,4-diaminopteridin-6-yl)methyl](methyl)amino}phenyl)formamido]pentanedioic acid
Chemical Formula C20H22N8O5
Chemical Structure Structure
CAS Registry Number 59-05-2
InChI Identifier InChI=1S/C20H22N8O5/c1-28(9-11-8-23-17-15(24-11)16(21)26-20(22)27-17)12-4-2-10(3-5-12)18(31)25-13(19(32)33)6-7-14(29)30/h2-5,8,13H,6-7,9H2,1H3,(H,25,31)(H,29,30)(H,32,33)(H4,21,22,23,26,27)
InChI Key InChIKey=FBOZXECLQNJBKD-UHFFFAOYSA-N
PubChem Compound ID 126941 Link Image
KEGG ID C01937 Link Image
UniProt ID Not Available
OMIM ID Not Available
ChEBI ID 6837 Link Image
BioCyc ID CPD-6041 Link Image
SuperToxic ID Not Available
CTD ID D008727 Link Image
Stitch ID Methotrexate Link Image
DrugBank ID DB00563 Link Image
PDB ID 1MVT Link Image
ACToR ID Not Available
Wikipedia Link http://en.wikipedia.org/wiki/Methotrexate Link Image
Monoisotopic Mass 454.171316
MOL File Show
PDB File Show
SDF File Show
SMILES CN(CC1=CN=C2N=C(N)N=C(N)C2=N1)C1=CC=C(C=C1)C(=O)NC(CCC(O)=O)C(O)=O
Appearance Orange-brown, crystalline powder (S191).
Melting Point 195 oC
Solubility 2600 mg/L
Predicted LogP -0.5062
Route of Exposure Inhalation (S498); dermal (S498); intravenous (S498)
Mechanism of Action Methotrexate anti-tumor activity is a result of the inhibition of folic acid reductase, leading to inhibition of DNA synthesis and inhibition of cellular replication. The mechanism involved in its activity against rheumatoid arthritis is not known.
Metabolism After absorption, methotrexate undergoes hepatic and intracellular metabolism to form methotrexate polyglutamate, metabolites which by hydrolysis may be converted back to methotrexate. Methotrexate polyglutamates inhibit dihydrofolate reductase and thymidylate synthetase. Small amounts of these polyglutamate metabolites may remain in tissues for extended periods; the retention and prolonged action of these active metabolites vary among different cells, tissues, and tumors. In addition, small amounts of methotrexate polyglutamate may be converted to 7-hydroxymethotrexate; accumulation of this metabolite may become substantial following administration of high doses of methotrexate, since the aqueous solubility of 7-hydroxymethotrexate is threefold to fivefold lower than that of the parent compound. Following oral administration of methotrexate, the drug also is partially metabolized by the intestinal flora. Renal excretion is the primary route of elimination, and is dependent upon dosage and route of administration (S499).
Toxicity Values LD50: 43 mg/kg (Oral, Rat) (S405)
Lethal Dose Not Available
Carcinogenicity (IARC Classification) 3, not classifiable as to its carcinogenicity to humans. (R264)
Uses/Sources For the treatment of gestational choriocarcinoma, chorioadenoma destruens and hydatidiform mole. Also for the treatment of severe psoriasis and severe, active, classical or definite rheumatoid arthritis (S405).
Minimum Risk Level Not Available
Health Effects A small percentage of patients develop hepatitis, and there is an increased risk of pulmonary fibrosis where dry cough can be an important sign. The higher doses of methotrexate often used in cancer chemotherapy can cause toxic effects to the rapidly-dividing cells of bone marrow and gastrointestinal mucosa. The resulting myelosuppression and mucositis are often prevented (termed Leucovorin "rescue"- as this is the folic acid based drug used) (S502).
Symptoms Symptoms of overdose include bone marrow suppression and gastrointestinal toxicity.
Treatment Administer charcoal as a slurry. Consider gastric lavage after ingestion of a potentially life-threatening amount of poison if it can be performed soon after ingestion (generally within 1 hour). Protect airway by placement in Trendelenburg and left lateral decubitus position or by endotracheal intubation. Control any seizures first. Glucarpidase has been used intravenously in combination with thymidine and leucovorin to treat methotrexate toxicity. (R383)
General References
  • V722 - Johnston A, Gudjonsson JE, Sigmundsdottir H, Ludviksson BR, Valdimarsson H: The anti-inflammatory action of methotrexate is not mediated by lymphocyte apoptosis, but by the suppression of activation and adhesion molecules. Clin Immunol. 2005 Feb;114(2):154-63. [PubMed Link Image]
  • R264 - International Agency for Research on Cancer (2009). IARC Monographs on the Evaluation of Carcinogenic Risks to Humans.
  • R383 - Rumack BH (2009). POISINDEX(R) Information System. Englewood, CO: Micromedex, Inc. CCIS Volume 141, edition expires Aug, 2009.
  • S499 - McEvoy GK (ed) (2005). American Hospital Formulary Service - Drug Information 2005. Bethesda, MD: American Society of Health-System Pharmacists, Inc.
  • S191 - Lewis RJ Sr. (ed) (1997). Hawley's Condensed Chemical Dictionary. 13th ed. New York, NY: Van Nostrand Rheinhold Co.
  • V720 - Drugs.com
  • S405 - DrugBank: a knowledgebase for drugs, drug actions and drug targets. Wishart DS, Knox C, Guo AC, Cheng D, Shrivastava S, Tzur D, Gautam B, Hassanali M. Nucleic Acids Res. 2008 Jan;36(Database issue):D901-6. [PubMed Link Image]
  • S498 - Sessink PJM, , Boer KA, Scheefhaals APH, Anzion RBM, Bos RP. Occupational exposure to antineoplastic agents at several departments in a hospital: Environmental contamination and excretion of cyclophosphamide and ifosfamide in urine of exposed workers. Int Arch Occup Environ Health 1992;64:105-112. [PubMed Link Image]
  • S502 - Wikipedia. Methotrexate. Last Updated 31 July 2009.
  • V721 - Klareskog L, van der Heijde D, de Jager JP, Gough A, Kalden J, Malaise M, Martin Mola E, Pavelka K, Sany J, Settas L, Wajdula J, Pedersen R, Fatenejad S, Sanda M: Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial. Lancet. 2004 Feb 28;363(9410):675-81. [PubMed Link Image]
Targets
  1. Dihydrofolate reductase
  2. Serum albumin
Target 1 [top]
Target 1 ID 1213
Target 1 Name Dihydrofolate reductase
Target 1 Mechanism of Action Methotrexate anti-tumor activity is a result of the inhibition of folic acid reductase, leading to inhibition of DNA synthesis and inhibition of cellular replication. The mechanism involved in its activity against rheumatoid arthritis is not known.
Target 1 Description 5,6,7,8-tetrahydrofolate + NADP(+) = 7,8- dihydrofolate + NADPH
Target 1 Synonyms Not Available
Target 1 Gene Name DHFR
Target 1 Protein Sequence >Dihydrofolate reductase 
MVGSLNCIVAVSQNMGIGKNGDLPWPPLRNEFRYFQRMTTTSSVEGKQNLVIMGKKTWFS
IPEKNRPLKGRINLVLSRELKEPPQGAHFLSRSLDDALKLTEQPELANKVDMVWIVGGSS
VYKEAMNHPGHLKLFVTRIMQDFESDTFFPEIDLEKYKLLPEYPGVLSDVQEEKGIKYKF
EVYEKND
Target 1 Number of Residues 187
Target 1 Molecular Weight 21452.6
Target 1 Theoretical pI 7.60
Target 1 GO Classification
Function
binding
cofactor binding
coenzyme binding
NADP binding
catalytic activity
oxidoreductase activity
oxidoreductase activity, acting on the CH-NH group of donors
oxidoreductase activity, acting on the CH-NH group of donors, NAD or NADP as acceptor
dihydrofolate reductase activity
Process
nucleobase, nucleoside, nucleotide and nucleic acid metabolism
nucleotide metabolism
nucleotide biosynthesis
physiological process
metabolism
cellular metabolism
amino acid and derivative metabolism
amino acid metabolism
serine family amino acid metabolism
glycine metabolism
glycine biosynthesis
Component
Not Available
Target 1 General Function Coenzyme transport and metabolism
Target 1 Pathways Cofactor biosynthesis; tetrahydrofolate biosynthesis; 5,6,7,8-tetrahydrofolate from 7,8-dihydrofolate:step 1/1
Target 1 Reactions Not Available
Target 1 Signals
  • None
Target 1 Transmembrane Regions
  • None
Target 1 Essentiality Non Essential
Target 1 Domain Function PF00186:DHFR_1
Target 1 GenBank ID Protein Not Available
Target 1 UniProtKB ID P00374 Link Image
Target 1 Cellular Location Not Available
Target 1 Gene Sequence >564 bp 
GGGGGGGGGCGGAGGTCCTCCCGCTGCTGTCATGGTTGGTTCGCTAAACTGCATCGTCGC
TGTGTCCCAGAACATGGGCATCGGCAAGAACGGGGACCTGCCCTGGCCACCGCTCAGGAA
TGAATTCAGATATTTCCAGAGAATGACCACAACCTCTTCAGTAGAAGGTAAACAGAATCT
GGTGATTATGGGTAAGAAGACCTGGTTCTCCATTCCTGAGAAGAATCGACCTTTAAAGGG
TAGAATTAATTTAGTTCTCAGCAGAGAACTCAAGGAACCTCCACAAGGAGCTCATTTTCT
TTCCAGAAGTCTAGATGATGCCTTAAAACTTACTGAACAACCAGAATTAGCAAATAAAGT
AGACATGGTCTGGATAGTTGGTGGCAGTTCTGTTTATAAGGAAGCCATGAATCACCCAGG
CCATCTTAAACTATTTGTGACAAGGATCATGCAAGACTTTGAAAGTGACACGTTTTTTCC
AGAAATTGATTTGGAGAAATATAAACTTCTGCCAGAATACCCAGGTGTTCTCTCTGATGT
CCAGGAGGAGAAAGGCATTAAGTA
Target 1 GenBank Gene ID Not Available
Target 1 GeneCard ID DHFR Link Image
Target 1 GenAtlas ID DHFR Link Image
Target 1 HGNC ID HGNC:2861 Link Image
Target 1 Chromosome Location Not Available
Target 1 Locus 5q11.2-q13.2
Target 1 SNPs SNPJam Report Link Image
Target 1 Toxin References
  • V727 - Assaraf YG: Molecular basis of antifolate resistance. Cancer Metastasis Rev. 2007 Mar;26(1):153-81. [PubMed Link Image]
  • S918 - Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed Link Image]
  • V726 - Bennett B, Langan P, Coates L, Mustyakimov M, Schoenborn B, Howell EE, Dealwis C: Neutron diffraction studies of Escherichia coli dihydrofolate reductase complexed with methotrexate. Proc Natl Acad Sci U S A. 2006 Dec 5;103(49):18493-8. Epub 2006 Nov 27. [PubMed Link Image]
  • V725 - Al-Rashood ST, Aboldahab IA, Nagi MN, Abouzeid LA, Abdel-Aziz AA, Abdel-Hamide SG, Youssef KM, Al-Obaid AM, El-Subbagh HI: Synthesis, dihydrofolate reductase inhibition, antitumor testing, and molecular modeling study of some new 4(3H)-quinazolinone analogs. Bioorg Med Chem. 2006 Dec 15;14(24):8608-21. Epub 2006 Sep 12. [PubMed Link Image]
  • V724 - Uga H, Kuramori C, Ohta A, Tsuboi Y, Tanaka H, Hatakeyama M, Yamaguchi Y, Takahashi T, Kizaki M, Handa H: A new mechanism of methotrexate action revealed by target screening with affinity beads. Mol Pharmacol. 2006 Nov;70(5):1832-9. Epub 2006 Aug 25. [PubMed Link Image]
  • V723 - Totani K, Matsuo I, Ihara Y, Ito Y: High-mannose-type glycan modifications of dihydrofolate reductase using glycan-methotrexate conjugates. Bioorg Med Chem. 2006 Aug 1;14(15):5220-9. Epub 2006 May 2. [PubMed Link Image]
Target 1 General References 6323448; 6687716; 6235374; 15489334; 3383852; 2248959; 9374868; 1731871
Target 2 [top]
Target 2 ID 250
Target 2 Name Serum albumin
Target 2 Mechanism of Action Methotrexate anti-tumor activity is a result of the inhibition of folic acid reductase, leading to inhibition of DNA synthesis and inhibition of cellular replication. The mechanism involved in its activity against rheumatoid arthritis is not known.
Target 2 Description Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloidal osmotic pressure of blood
Target 2 Synonyms Not Available
Target 2 Gene Name ALB
Target 2 Protein Sequence >Serum albumin 
MKWVTFISLLFLFSSAYSRGVFRRDAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQCPF
EDHVKLVNEVTEFAKTCVADESAENCDKSLHTLFGDKLCTVATLRETYGEMADCCAKQEP
ERNECFLQHKDDNPNLPRLVRPEVDVMCTAFHDNEETFLKKYLYEIARRHPYFYAPELLF
FAKRYKAAFTECCQAADKAACLLPKLDELRDEGKASSAKQRLKCASLQKFGERAFKAWAV
ARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDLLECADDRADLAKYICENQDSISSKLK
ECCEKPLLEKSHCIAEVENDEMPADLPSLAADFVESKDVCKNYAEAKDVFLGMFLYEYAR
RHPDYSVVLLLRLAKTYETTLEKCCAAADPHECYAKVFDEFKPLVEEPQNLIKQNCELFE
QLGEYKFQNALLVRYTKKVPQVSTPTLVEVSRNLGKVGSKCCKHPEAKRMPCAEDYLSVV
LNQLCVLHEKTPVSDRVTKCCTESLVNRRPCFSALEVDETYVPKEFNAETFTFHADICTL
SEKERQIKKQTALVELVKHKPKATKEQLKAVMDDFAAFVEKCCKADDKETCFAEEGKKLV
AASQAALGL
Target 2 Number of Residues 609
Target 2 Molecular Weight 69365.9
Target 2 Theoretical pI 6.21
Target 2 GO Classification
Function
transporter activity
carrier activity
Process
physiological process
cellular physiological process
transport
Component
extracellular region
extracellular space
Target 2 General Function Involved in antioxidant activity
Target 2 Pathways REACT_604-Hemostasis;
Target 2 Reactions Not Available
Target 2 Signals
  • 1-18
Target 2 Transmembrane Regions
  • None
Target 2 Essentiality Non Essential
Target 2 Domain Function PF00273:Serum_albumin
Target 2 GenBank ID Protein Not Available
Target 2 UniProtKB ID P02768 Link Image
Target 2 Cellular Location Secreted
Target 2 Gene Sequence >1830 bp 
ATGAAGTGGGTAACCTTTATTTCCCTTCTTTTTCTCTTTAGCTCGGCTTATTCCAGGGGT
GTGTTTCGTCGAGATGCACACAAGAGTGAGGTTGCTCATCGGTTTAAAGATTTGGGAGAA
GAAAATTTCAAAGCCTTGGTGTTGATTGCCTTTGCTCAGTATCTTCAGCAGTGTCCATTT
GAAGATCATGTAAAATTAGTGAATGAAGTAACTGAATTTGCAAAAACATGTGTTGCTGAT
GAGTCAGCTGAAAATTGTGACAAATCACTTCATACCCTTTTTGGAGACAAATTATGCACA
GTTGCAACTCTTCGTGAAACCTATGGTGAAATGGCTGACTGCTGTGCAAAACAAGAACCT
GGGAGAAATGAATGCTTCTTGCAACACAAAGATGACAACCCAAACCTCCCCCGATTGGTG
AGACCAGAGGTTGATGTGATGTGCACTGCTTTTCATGACAATGAAGAGACATTTTTGAAA
AAATACTTATATGAAATTGCCAGAAGACATCCTTACTTTTATGCCCCGGAACTCCTTTTC
TTTGCTAAAAGGTATAAAGCTGCTTTTACAGAATGTTGCCAAGCTGCTGATAAAGCTGCC
TGCCTGTTGCCAAAGCTCGATGAACTTCGGGATGAAGGGAAGGCTTCGTCTGCCAAACAG
AGACTCAAGTGTGCCAGTCTCCAAAAATTTGGAGAAAGAGCTTTCAAAGCATGGGCAGTA
GCTCGCCTGAGCCAGAGATTTCCCAAAGCTGAGTTTGCAGAAGTTTCCAAGTTAGTGACA
GATCTTACCAAAGTCCACACGGAATGCTGCCATGGAGATCTGCTTGAATGTGCTGATGAC
AGGGCGGACCTTGCCAAGTATATCTGTGAAAATCAAGATTCGATCTCCAGTAAACTGAAG
GAATGCTGTGAAAAACCTCTGTTGGAAAAATCCCACTGCATTGCCGAAGTGGAAAATGAT
GAGATGCCTGCTGACTTGCCTTCATTAGCTGCTGATTTTGTTGAAAGTAAGGATGTTTGC
AAAAACTATGCTGAGGCAAAGGATGTCTTCTTGGGCATGTTTTTGTATGAATATGCAAGA
AGGCATCCTGATTACTCTGTCGTGCTGCTGCTGAGACTTGCCAAGACATATGAAACCACT
CTAGAGAAGTGCTGTGCCGCTGCAGATCCTCATGAATGCTATGCCAAAGTGTTCGATGAA
TTTAAACCTCTTGTGGAAGAGCCTCAGAATTTAATCAAACAAAATTGTGAGCTTTTTGAG
CAGCTTGGAGAGTACAAATTCCAGAATGCGCTGTTAGTTCGTTACACCAAGAAAGTACCC
GAAGTGTCAACTCCAACTCTTGTAGAGGTCTCAAGAAACCTAGGAAAAGTGGGCAGCAAA
TGTTGTAAACATCCTGAAGCAAAAAGAATGCCCTGTGCAGAAGACTATCTATCCGTGGTC
CTGAACCAGTTATGTGTGTTGCATGAGAAAACGCCAGTAAGTGACAGAGTCACCAAATGC
TGCACAGAATCCTTGGTGAACAGGCGACCATGCTTTTCAGCTCTGGAAGTCGATGAAACA
TACGTTCCCAAAGAGTTTAATGCTGAAACATTCACCTTCCATGCAGATATATGCACACTT
TCTGAGAAGGAGAGACAAATCAAGAAACAAACTGCACTTGTTGAGCTCGTGAAACACAAG
CCCAAGGCAACAAAAGAGCAACTGAAAGCTGTTATGGATGATTTCGCTGCTTTTGTAGAG
AAGTGCTGCAAGGCTGACGATAAGGAGACCTGCTTTGCCGAGGAGGGTAAAAAACTTGTT
GCTGCAAGTCAAGCTGCCTTAGGCTTATAA
Target 2 GenBank Gene ID Not Available
Target 2 GeneCard ID ALB Link Image
Target 2 GenAtlas ID ALB Link Image
Target 2 HGNC ID HGNC:399 Link Image
Target 2 Chromosome Location Not Available
Target 2 Locus 4q11-q13
Target 2 SNPs SNPJam Report Link Image
Target 2 Toxin References
  • V732 - Warnecke A, Fichtner I, Sass G, Kratz F: Synthesis, cleavage profile, and antitumor efficacy of an albumin-binding prodrug of methotrexate that is cleaved by plasmin and cathepsin B. Arch Pharm (Weinheim). 2007 Aug;340(8):389-95. [PubMed Link Image]
  • V729 - Diskin CJ, Stokes TJ, Dansby LM, Radcliff L, Carter TB: Removal of methotrexate by peritoneal dialysis and hemodialysis in a single patient with end-stage renal disease. Am J Med Sci. 2006 Sep;332(3):156-8. [PubMed Link Image]
  • V731 - Kratz F, Abu Ajaj K, Warnecke A: Anticancer carrier-linked prodrugs in clinical trials. Expert Opin Investig Drugs. 2007 Jul;16(7):1037-58. [PubMed Link Image]
  • V730 - Xie WJ, Feng YP, Cao SL, Zhao YF: [Study of the interaction between methotrexate and bovine serum albumin by spectrometry] Guang Pu Xue Yu Guang Pu Fen Xi. 2006 Oct;26(10):1876-9. [PubMed Link Image]
  • V728 - Bolling C, Graefe T, Lubbing C, Jankevicius F, Uktveris S, Cesas A, Meyer-Moldenhauer WH, Starkmann H, Weigel M, Burk K, Hanauske AR: Phase II study of MTX-HSA in combination with Cisplatin as first line treatment in patients with advanced or metastatic transitional cell carcinoma. Invest New Drugs. 2006 Nov;24(6):521-7. [PubMed Link Image]
Target 2 General References 6171778; 6275391; 3009475; 11483580

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