Irinotecan Pathway (Canis familiaris)

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1, 2DiarrheaLiver CellModel human liver cell showing blood, bile and intestinal compartments, indicating tissueinvolvment of genes in the irinotecan pathway.NeutropeniaIntestineABCC1CES2CYP3A4CES1ABCC1CES1SN-38NPC1ABCC1IrinotecanCES1ABCC2UGT1A6SN-38GM4CES2ABCC2CES1CYP3A4UGT1A6ABCC2SN-38UGT1A10UGT1A9UGT1A1IrinotecanSN-38CES2CYP3A5ABCG2SN-38GAPCUGT1A1CES2IrinotecanCYP3A5CYP3A4BCHE


Description

This pathway shows the biotransformation of the chemotherapy prodrug irinotecan to form the active metabolite SN-38, an inhibitor of DNA topoisomerase I. SN-38 is primarily metabolized to the inactive SN-38 glucuronide by UGT1A1, the isoform catalyzing bilirubin glucuronidation. Irinotecan is used in the treatment of metastatic colorectal cancer, small cell lung cancer and several other solid tumors. There is large interpatient variability in response to irinotecan, as well as severe side effects such as diarrhea and neutropenia, which might be explained in part by genetic variation in the metabolic enzymes and transporters depicted here. Well-known variants to effect this pathway are the promoter polymorphic repeat in UGT1A1 (UGT1A1*28) and the 1236C>T polymorphism in ABCB1. While UGT1A1*28 genotype has been associated with toxicity, further evidence is needed to describe the roles of ABCB1 variants in toxicity.

Source: PharmGkb

Comments

HomologyConvert 
This pathway was inferred from Homo sapiens pathway WP229(r26589) with a 51% conversion rate.

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Ontology Terms

 

Bibliography

  1. Desai AA, Innocenti F, Ratain MJ; ''UGT pharmacogenomics: implications for cancer risk and cancer therapeutics.''; Pharmacogenetics, 2003 PubMed Europe PMC
  2. Mathijssen RH, Marsh S, Karlsson MO, Xie R, Baker SD, Verweij J, Sparreboom A, McLeod HL; ''Irinotecan pathway genotype analysis to predict pharmacokinetics.''; Clin Cancer Res, 2003 PubMed Europe PMC

History

View all...
CompareRevisionActionTimeUserComment
93222view17:39, 4 August 2017AlexanderPicoAdded ChEBI ID for APC metabolite
93197view15:47, 2 August 2017DeSlChanged several gene nodes to metabolite nodes, added IDs for them.
68768view16:03, 7 July 2013EgonwChanged the PubChem compound ID of irinotecan, following the discussion of WP961 -> http://wikipathways.org/index.php/Thread:PubChem_ID_for_irinotecan_should_be_verified_%281%29
68608view23:33, 5 July 2013MaintBotUpdated to 2013 gpml schema
67408view10:57, 26 June 2013DdiglesOntology Term : 'irinotecan drug pathway' added !
40768view21:55, 1 March 2011MaintBotRemoved redundant pathway information and comments
35505view13:15, 12 February 2010ThomasModified description
35504view13:14, 12 February 2010Thomasadded literature, removed genmapp comments
34037view18:50, 9 December 2009MaintBotAutomatic update of empty xrefs
32273view13:05, 15 August 2009MaintBotFixed text labels
31807view12:20, 14 August 2009MaintBotFixed group labels
31301view20:11, 13 August 2009MaintBotFixed text labels
30766view23:14, 29 July 2009MaintBotNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
ABCC1GeneProduct403453 (Entrez Gene)
ABCC2GeneProduct403632 (Entrez Gene)
ABCG2GeneProduct478472 (Entrez Gene)
APCMetaboliteCHEBI:80551 (ChEBI)
BCHEGeneProduct488143 (Entrez Gene)
CES1GeneProduct403643 (Entrez Gene)
CES2GeneProduct489769 (Entrez Gene)
CYP3A4GeneProduct1576 (Entrez Gene)
CYP3A5GeneProduct1577 (Entrez Gene)
IrinotecanMetabolite60838 (PubChem-compound)
M4Metabolitemolecular weight, 558
NPC1GeneProduct4864 (Entrez Gene)
SN-38MetaboliteCHEBI:8988 (ChEBI)
SN-38GMetaboliteCHEBI:8990 (ChEBI)
UGT1A10GeneProduct54575 (Entrez Gene)
UGT1A1GeneProduct54658 (Entrez Gene)
UGT1A6GeneProduct403629 (Entrez Gene)
UGT1A9GeneProduct54600 (Entrez Gene)

Annotated Interactions

No annotated interactions
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