Irinotecan Pathway (Rattus norvegicus)

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1, 2NeutropeniaIntestineModel human liver cell showing blood, bile and intestinal compartments, indicating tissueinvolvment of genes in the irinotecan pathway.DiarrheaLiver CellCYP3A4SN-38Ces2Abcg2BcheAbcc2SN-38RGD:621508Ces2CYP3A5Ugt1a1RGD:621508RGD:621508UGT1A9Abcc2Abcc1SN-38GRGD:621508CYP3A5SN-38UGT1A10Abcc2SN-38GCYP3A4Abcc1Ugt1a1NPC1IrinotecanCes2CYP3A4M4IrinotecanIrinotecanAbcc1Ugt1a6Ces2APCUgt1a6


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

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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 Scholia
  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 Scholia

History

View all...
CompareRevisionActionTimeUserComment
93209view18:50, 3 August 2017AlexanderPicoAdded ChEBI ID for APC metabolite
93208view18:48, 3 August 2017AlexanderPicoReverted to version '08:33, 2 August 2017' by AlexanderPico
93207view18:46, 3 August 2017AlexanderPicomanually updated color to match geneproduct
93206view18:44, 3 August 2017AlexanderPicoChanged APC from Metabolite back to GeneProduct
93195view15:33, 2 August 2017DeSlAdded ID for NPC1
93194view15:31, 2 August 2017DeSlChanged several gene nodes to metabolite nodes, added IDs for them.
79805view16:30, 16 April 2015Mkutmonfixed unconnected lines
79333view11:59, 21 March 2015EgonwReplaced a gene name with its Entrez Gene identifier and removed some gene names as Entrez Gene identifier if they did not show a hit in the database.
79332view11:50, 21 March 2015EgonwIrinotecan is a compound, not a gene, and added the .@ChemSpider ID.
69405view19:00, 8 July 2013MaintBotUpdated to 2013 gpml schema
67409view10:57, 26 June 2013DdiglesOntology Term : 'irinotecan drug pathway' added !
41725view02:38, 2 March 2011MaintBotRemoved redundant pathway information and comments
35506view13:36, 12 February 2010Thomasconnected lines
35497view13:09, 12 February 2010Thomasremoved genmapp comment
35494view13:08, 12 February 2010ThomasModified description
35493view13:07, 12 February 2010Thomasadded literature, fixed label
34101view19:20, 9 December 2009MaintBotAutomatic update of empty xrefs
20943view11:30, 14 November 2008MaintBot[[Pathway:Rattus norvegicus:Irinotecan pathway PharmGKB]] moved to [[Pathway:WP124]]: Moved to stable identifier
8228view13:46, 7 January 2008MaintBot[[Pathway:Rat:Irinotecan pathway PharmGKB]] moved to [[Pathway:Rattus norvegicus:Irinotecan pathway PharmGKB]]: Renaming species
7734view16:14, 18 December 2007MaintBotfixed category names
7481view12:42, 4 November 2007MaintBotAdded categories to GPML
6570view22:20, 22 May 2007169.230.77.174gpml file for [[Rat:Irinotecan_pathway_PharmGKB]]

External references

DataNodes

View all...
NameTypeDatabase referenceComment
APCMetaboliteCHEBI:80551 (ChEBI)
Abcc1GeneProduct24565 (Entrez Gene)
Abcc2GeneProduct25303 (Entrez Gene)
Abcg2GeneProduct312382 (Entrez Gene)
BcheGeneProduct65036 (Entrez Gene)
CYP3A4GeneProduct1576 (Entrez Gene)
CYP3A5GeneProduct1577 (Entrez Gene)
Ces2GeneProduct171118 (Entrez Gene)
IrinotecanMetabolite54825 (Chemspider)
IrinotecanMetaboliteCHEBI:80630 (ChEBI)
M4Metabolitemolecular weight, 558
NPC1GeneProduct4864 (Entrez Gene)
RGD:621508GeneProduct29225 (Entrez Gene)
SN-38MetaboliteCHEBI:8988 (ChEBI)
SN-38GMetaboliteCHEBI:8990 (ChEBI)
UGT1A10GeneProduct54575 (Entrez Gene)
UGT1A9GeneProduct396552 (Entrez Gene)
Ugt1a1GeneProduct24861 (Entrez Gene)
Ugt1a6GeneProduct113992 (Entrez Gene)

Annotated Interactions

No annotated interactions

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