Irinotecan Pathway (Bos taurus)

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763, 11103, 1141, 2, 8, 133, 11512912Liver CellModel human liver cell showing blood, bile and intestinal compartments, indicating tissueinvolvment of genes in the irinotecan pathway.DiarrheaNeutropeniaIntestineCES2CYP3A4ABCC1UGT1A10UGT1A1IrinotecanABCC1CYP3A5CES1ABCC2CES1CES2UGT1A1CYP3A4CES1UGT1A9CES2M4SLCO1B1NPC1APCIrinotecanCYP3A4ABCC2SN-38IrinotecanCES1SN-38GABCC1SN-38SN-38CES2ABCC2SN-38GBCHEABCG2CYP3A5


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(68389) with a 82.0% conversion rate.

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Bibliography

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  1. Gagné JF, Montminy V, Belanger P, Journault K, Gaucher G, Guillemette C; ''Common human UGT1A polymorphisms and the altered metabolism of irinotecan active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38).''; Mol Pharmacol, 2002 PubMed Europe PMC
  2. Iyer L, Das S, Janisch L, Wen M, Ramírez J, Karrison T, Fleming GF, Vokes EE, Schilsky RL, Ratain MJ; ''UGT1A1*28 polymorphism as a determinant of irinotecan disposition and toxicity.''; Pharmacogenomics J, 2002 PubMed Europe PMC
  3. Sai K, Kaniwa N, Ozawa S, Sawada JI; ''A new metabolite of irinotecan in which formation is mediated by human hepatic cytochrome P-450 3A4.''; Drug Metab Dispos, 2001 PubMed Europe PMC
  4. Nozawa T, Minami H, Sugiura S, Tsuji A, Tamai I; ''Role of organic anion transporter OATP1B1 (OATP-C) in hepatic uptake of irinotecan and its active metabolite, 7-ethyl-10-hydroxycamptothecin: in vitro evidence and effect of single nucleotide polymorphisms.''; Drug Metab Dispos, 2005 PubMed Europe PMC
  5. Rajendra R, Gounder MK, Saleem A, Schellens JH, Ross DD, Bates SE, Sinko P, Rubin EH; ''Differential effects of the breast cancer resistance protein on the cellular accumulation and cytotoxicity of 9-aminocamptothecin and 9-nitrocamptothecin.''; Cancer Res, 2003 PubMed Europe PMC
  6. Desai AA, Innocenti F, Ratain MJ; ''UGT pharmacogenomics: implications for cancer risk and cancer therapeutics.''; Pharmacogenetics, 2003 PubMed Europe PMC
  7. Sai K, Kaniwa N, Itoda M, Saito Y, Hasegawa R, Komamura K, Ueno K, Kamakura S, Kitakaze M, Shirao K, Minami H, Ohtsu A, Yoshida T, Saijo N, Kitamura Y, Kamatani N, Ozawa S, Sawada J; ''Haplotype analysis of ABCB1/MDR1 blocks in a Japanese population reveals genotype-dependent renal clearance of irinotecan.''; Pharmacogenetics, 2003 PubMed Europe PMC
  8. Iyer L, King CD, Whitington PF, Green MD, Roy SK, Tephly TR, Coffman BL, Ratain MJ; ''Genetic predisposition to the metabolism of irinotecan (CPT-11). Role of uridine diphosphate glucuronosyltransferase isoform 1A1 in the glucuronidation of its active metabolite (SN-38) in human liver microsomes.''; J Clin Invest, 1998 PubMed Europe PMC
  9. Chen ZS, Furukawa T, Sumizawa T, Ono K, Ueda K, Seto K, Akiyama SI; ''ATP-Dependent efflux of CPT-11 and SN-38 by the multidrug resistance protein (MRP) and its inhibition by PAK-104P.''; Mol Pharmacol, 1999 PubMed Europe PMC
  10. 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 PubMed Europe PMC
  11. Santos A, Zanetta S, Cresteil T, Deroussent A, Pein F, Raymond E, Vernillet L, Risse ML, Boige V, Gouyette A, Vassal G; ''Metabolism of irinotecan (CPT-11) by CYP3A4 and CYP3A5 in humans.''; Clin Cancer Res, 2000 PubMed Europe PMC
  12. 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
  13. Jinno H, Saeki M, Saito Y, Tanaka-Kagawa T, Hanioka N, Sai K, Kaniwa N, Ando M, Shirao K, Minami H, Ohtsu A, Yoshida T, Saijo N, Ozawa S, Sawada J; ''Functional characterization of human UDP-glucuronosyltransferase 1A9 variant, D256N, found in Japanese cancer patients.''; J Pharmacol Exp Ther, 2003 PubMed Europe PMC

History

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CompareRevisionActionTimeUserComment
101977view20:02, 21 November 2018EgonwRemoved whitespace in PubMed identifiers.
93191view15:04, 2 August 2017DeSlAdded ID for SN-38G and added molecular weight for M4 (unknown metabolite)
93190view15:00, 2 August 2017DeSlAdded refrences for 3 genes (ABCC2, UGT1A10, UGT1A9)
93189view14:55, 2 August 2017DeSlChanged CheMBL compound IDs for irinotecan+SN-38 to ChEBI's
80765view15:25, 30 June 2015Mkutmonhomology conversion
68767view16:02, 7 July 2013EgonwAnd changed it another two times.
68766view16:00, 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.
67407view10:57, 26 June 2013DdiglesOntology Term : 'irinotecan drug pathway' added !
63392view00:04, 10 May 2013MaintBotUpdated to 2013 gpml schema
40565view19:32, 1 March 2011MaintBotRemoved redundant pathway information and comments
35503view13:13, 12 February 2010ThomasModified description
35502view13:12, 12 February 2010Thomasadded literature, removed genmapp comment
33803view00:18, 9 December 2009MaintBotAutomatic update of empty xrefs
32531view12:59, 17 August 2009MaintBotFixed text labels
32218view12:45, 15 August 2009MaintBotFixed text labels
31713view11:53, 14 August 2009MaintBotFixed group labels
31229view19:44, 13 August 2009MaintBotFixed text labels
30649view22:33, 29 July 2009MaintBotNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
ABCC1GeneProductENSBTAG00000021090 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4363
ABCC2GeneProduct1244 (Entrez Gene)
ABCG2GeneProductENSBTAG00000017704 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:9429
APCGeneProductENSBTAG00000018852 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:324
BCHEGeneProductENSBTAG00000011139 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:590
CES1GeneProductENSBTAG00000011021 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1066
CES2GeneProductENSBTAG00000005093 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:8824
CYP3A4GeneProductENSBTAG00000047379 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1576
CYP3A5GeneProductENSBTAG00000047379 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1577
IrinotecanMetaboliteCHEBI:80630 (ChEBI)
M4Metabolitemolecular weight, 558
NPC1GeneProductENSBTAG00000015195 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4864
SLCO1B1GeneProductENSBTAG00000022329 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:10599
SN-38MetaboliteCHEBI:8988 (ChEBI)
SN-38GMetaboliteCHEBI:8990 (ChEBI)
UGT1A10GeneProduct54575 (Entrez Gene)
UGT1A1GeneProductENSBTAG00000026181 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:54658
UGT1A9GeneProduct54600 (Entrez Gene)

Annotated Interactions

No annotated interactions
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