Irinotecan pathway (WP229)

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: [http://www.pharmgkb.org/search/pathway/irinotecan/liver.jsp PharmGkb] Proteins on this pathway have targeted assays available via the [https://assays.cancer.gov/available_assays?wp_id=WP229 CPTAC Assay Portal]
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Authors

MaintBot, Thomas, AlexanderPico, Khanspers, MartijnVanIersel, Ddigles, Egonw, DeSl, and Eweitz

Cited In

Organism

Homo sapiens

Communities

CPTAC Inborn Errors of Metabolism (IEM) Pathways

Annotations

Pathway Ontology: irinotecan drug pathway

Cell Type Ontology: hepatocyte enterocyte

Disease Ontology: diarrhea cancer neutropenia Niemann-Pick disease type C1

Participants

Label Type Compact Identifier
SN-38G Metabolite chebi:8990
UGT1A10 GeneProduct ncbigene:54575
ABCC2 GeneProduct ncbigene:1244
Irinotecan Metabolite chebi:80630
NPC1 GeneProduct ncbigene:4864
CES2 GeneProduct ncbigene:8824
CES1 GeneProduct ncbigene:1066
CYP3A4 GeneProduct ncbigene:1576
BCHE GeneProduct ncbigene:590
ABCC1 GeneProduct ncbigene:4363
CES2 GeneProduct ncbigene:8824
SN-38 Metabolite chebi:8988
SN-38G Metabolite chebi:8990
SN-38 Metabolite chebi:8988
CES1 GeneProduct ncbigene:1066
ABCC2 GeneProduct ncbigene:1244
ABCC1 GeneProduct ncbigene:4363
UGT1A9 GeneProduct ncbigene:54600
CYP3A4 GeneProduct ncbigene:1576
APC Metabolite pubchem.compound:10077584
CES1 GeneProduct ncbigene:1066
UGT1A1 GeneProduct ncbigene:54658
ABCC2 GeneProduct ncbigene:1244
UGT1A1 GeneProduct ncbigene:54658
ABCC1 GeneProduct ncbigene:4363
M4 Metabolite None
CYP3A5 GeneProduct ncbigene:1577
SN-38 Metabolite chebi:8988
CES2 GeneProduct ncbigene:8824
ABCG2 GeneProduct ncbigene:9429
Irinotecan Metabolite chebi:80630
CYP3A5 GeneProduct ncbigene:1577
CES1 GeneProduct ncbigene:1066
SLCO1B1 GeneProduct ncbigene:10599
Irinotecan Metabolite chebi:80630
CES2 GeneProduct ncbigene:8824
CYP3A4 GeneProduct ncbigene:1576

References

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  2. Morton CL, Wadkins RM, Danks MK, Potter PM. The anticancer prodrug CPT-11 is a potent inhibitor of acetylcholinesterase but is rapidly catalyzed to SN-38 by butyrylcholinesterase. Cancer Res. 1999 Apr 1;59(7):1458–63. PubMed Europe PMC Scholia
  3. Chen ZS, Furukawa T, Sumizawa T, Ono K, Ueda K, Seto K, et al. ATP-Dependent efflux of CPT-11 and SN-38 by the multidrug resistance protein (MRP) and its inhibition by PAK-104P. Mol Pharmacol. 1999 May;55(5):921–8. PubMed Europe PMC Scholia
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