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]

Authors

Unknown , Thomas Kelder , Alex Pico , Kristina Hanspers , Martijn Van Iersel , Daniela Digles , Egon Willighagen , Denise Slenter , and Eric Weitz

Cited In

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Organism

Homo sapiens

Communities

CPTAC Inborn Errors of Metabolism (IEM) Pathways

Annotations

Disease Ontology: neutropenia diarrhea cancer

Cell Type Ontology: hepatocyte enterocyte

Pathway Ontology: irinotecan drug pathway

Participants

References

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