Irinotecan pathway (Canis familiaris)

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1, 2Model human liver cell showing blood, bile and intestinal compartments, indicating tissueinvolvment of genes in the irinotecan pathway.DiarrheaNeutropeniaIntestineLiver CellNPCABCC1ABCG2SN-38UGT1A6ABCC2CYP3A4CES2ABCC1UGT1A1ABCC2CYP3A4SN-38CES1CES1SN-38ABCC1SN-38UGT1A1IrinotecanCYP3A4ABCC2CES2M4CES1CYP3A5UGT1A9CYP3A5UGT1A10CES1CES2IrinotecanCES2APCUGT1A6BCHEIrinotecanSN-38G


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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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

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CompareRevisionActionTimeUserComment
116615view09:59, 9 May 2021EweitzModified description
116610view09:42, 9 May 2021EweitzModified title
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

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NameTypeDatabase referenceComment
ABCC1GeneProduct403453 (Entrez Gene)
ABCC2GeneProduct403632 (Entrez Gene)
ABCG2GeneProduct478472 (Entrez Gene)
APCGeneProduct479139 (Entrez Gene)
BCHEGeneProduct488143 (Entrez Gene)
CES1GeneProduct403643 (Entrez Gene)
CES2GeneProduct489769 (Entrez Gene)
CYP3A4GeneProduct
CYP3A5GeneProduct
IrinotecanMetabolite60838 (PubChem-compound)
M4GeneProduct
NPCGeneProduct
SN-38GeneProduct
SN-38GGeneProduct
UGT1A1GeneProduct
UGT1A10GeneProduct
UGT1A6GeneProduct403629 (Entrez Gene)
UGT1A9GeneProduct

Annotated Interactions

No annotated interactions
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