Irinotecan pathway (WP124)
Rattus norvegicus
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]
Authors
Thomas Kelder , Daniela Digles , Egon Willighagen , Martina Summer-Kutmon , Denise Slenter , Alex Pico , Eric Weitz , and AmadeoActivity
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Organisms
Rattus norvegicusCommunities
Annotations
Disease Ontology
diarrhea cancer neutropeniaPathway Ontology
irinotecan drug pathwayLabel | Type | Compact URI | Comment |
---|---|---|---|
Irinotecan | Metabolite | chemspider:54825 | |
Irinotecan | Metabolite | chebi:80630 | |
SN-38 | Metabolite | chebi:8988 | |
SN-38G | Metabolite | chebi:8990 | |
APC | Metabolite | chebi:80551 | |
Abcc1 | GeneProduct | ncbigene:24565 | |
Abcg2 | GeneProduct | ncbigene:312382 | |
Abcc2 | GeneProduct | ncbigene:25303 | |
Ces2 | GeneProduct | ncbigene:171118 | |
RGD:621508 | GeneProduct | ncbigene:29225 | |
CYP3A4 | GeneProduct | ncbigene:1576 | |
Ugt1a6 | GeneProduct | ncbigene:113992 | |
Ugt1a1 | GeneProduct | ncbigene:24861 | |
UGT1A10 | GeneProduct | ncbigene:54575 | |
CYP3A5 | GeneProduct | ncbigene:1577 | |
UGT1A9 | GeneProduct | ncbigene:396552 | |
NPC1 | GeneProduct | ncbigene:4864 | |
Bche | GeneProduct | ncbigene:65036 |
References
- UGT pharmacogenomics: implications for cancer risk and cancer therapeutics. Desai AA, Innocenti F, Ratain MJ. Pharmacogenetics. 2003 Aug;13(8):517–23. PubMed Europe PMC Scholia
- Irinotecan pathway genotype analysis to predict pharmacokinetics. Mathijssen RHJ, Marsh S, Karlsson MO, Xie R, Baker SD, Verweij J, et al. Clin Cancer Res. 2003 Aug 15;9(9):3246–53. PubMed Europe PMC Scholia