Irinotecan Pathway (Homo sapiens)

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8104, 71, 2, 12, 1394, 73116854, 7NeutropeniaIntestineDiarrheaModel human liver cell showing blood, bile and intestinal compartments, indicating tissueinvolvment of genes in the irinotecan pathway.Liver CellSN-38GABCC1CYP3A5NPC1M4CYP3A4SN-38CES2ABCC2UGT1A9ABCC1IrinotecanUGT1A1UGT1A10IrinotecanAPCSN-38CES2IrinotecanUGT1A1CES1CES1ABCC1ABCG2CES1BCHECYP3A4ABCC2SN-38SN-38GCYP3A4CES2CES1CES2ABCC2CYP3A5SLCO1B1


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

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Bibliography

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  1. 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
  2. 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
  3. 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
  4. 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
  5. Desai AA, Innocenti F, Ratain MJ; ''UGT pharmacogenomics: implications for cancer risk and cancer therapeutics.''; Pharmacogenetics, 2003 PubMed
  6. 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
  7. 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
  8. 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
  9. 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
  10. 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
  11. 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
  12. 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
  13. 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

History

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CompareRevisionActionTimeUserComment
101954view21:30, 20 November 2018EgonwRemoved whitespace in PubMed identifiers.
96294view15:59, 7 March 2018DeSlChanged layout
96094view19:23, 15 February 2018EgonwFixed data node typing.
96057view16:51, 15 February 2018EgonwFixed the APC identifier.
96003view09:23, 15 February 2018DeSlChanged literature ref (couldn't recognize symbol "í"
96002view09:22, 15 February 2018DeSlChanged literature ref (couldn't recognize symbol "é")
96001view09:20, 15 February 2018DeSlRemoved licence number
96000view09:16, 15 February 2018DeSlChnaged visualisation of enzymes, small layout changes.
93199view15:56, 2 August 2017DeSlReplaced NPC1 node, since the appearance was of metabolite, even though the node was a gene...
93196view15:39, 2 August 2017DeSlChamged appaerence of NPC1 gene (looked like metabolite)
93192view15:08, 2 August 2017DeSlAdded ID for SN-38G and added molecular weight for M4 (unknown metabolite)
93188view14:52, 2 August 2017DeSlAdded CHEBI: for IDnumber of SN-38
93187view14:51, 2 August 2017DeSlChanged CheMBL compound IDs for irinotecan+SN-38 to ChEBI's
68389view10:22, 4 July 2013EgonwFixed the DataNode type of two nodes with gene identifiers.
67410view10:58, 26 June 2013DdiglesOntology Term : 'irinotecan drug pathway' added !
63225view21:03, 8 May 2013MaintBotUpdating gpml version
46359view20:12, 19 January 2012KhanspersOntology Term : 'enterocyte' added !
46358view20:11, 19 January 2012KhanspersOntology Term : 'hepatocyte' added !
46357view20:09, 19 January 2012KhanspersOntology Term : 'diarrhea' added !
46356view20:09, 19 January 2012KhanspersOntology Term : 'neutropenia' added !
46355view20:08, 19 January 2012KhanspersOntology Term : 'DOID:0000405' removed !
46354view20:07, 19 January 2012KhanspersFInished references
46353view20:04, 19 January 2012KhanspersCleaned up references
46352view20:00, 19 January 2012KhanspersAdded references
46351view19:37, 19 January 2012KhanspersChanged metaboliote colors, added xrefs
46343view01:07, 19 January 2012Khansperschanged layout and added xrefs
44876view10:03, 6 October 2011MartijnVanIerselOntology Term : 'cancer' added !
41131view23:38, 1 March 2011MaintBotRemoved redundant pathway information and comments
38882view18:57, 24 September 2010Khanspers
38757view22:45, 23 September 2010KhanspersChanged compartments and line types
35492view13:04, 12 February 2010ThomasModified description
35491view13:03, 12 February 2010Thomasadded literature, removed genmapp comments
34493view22:13, 16 December 2009KhanspersAdded connectors
34492view22:08, 16 December 2009Khanspersminor edits
34482view18:39, 10 December 2009MaintBotAutomatic update of empty xrefs
32364view13:43, 15 August 2009MaintBotFixed text labels
32003view13:17, 14 August 2009MaintBotFixed group labels
26589view18:27, 10 December 2008AlexanderPico
21159view11:30, 14 November 2008MaintBot[[Pathway:Homo sapiens:Irinotecan pathway PharmGKB]] moved to [[Pathway:WP229]]: Moved to stable identifier
13987view14:22, 20 May 2008Thomas
8224view13:46, 7 January 2008MaintBot[[Pathway:Human:Irinotecan pathway PharmGKB]] moved to [[Pathway:Homo sapiens:Irinotecan pathway PharmGKB]]: Renaming species
7732view16:14, 18 December 2007MaintBotfixed category names
7479view12:42, 4 November 2007MaintBotAdded categories to GPML
6346view22:18, 22 May 2007169.230.77.174gpml file for [[Human:Irinotecan_pathway_PharmGKB]]

External references

DataNodes

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NameTypeDatabase referenceComment
ABCC1GeneProduct4363 (Entrez Gene)
ABCC2GeneProduct1244 (Entrez Gene)
ABCG2GeneProduct9429 (Entrez Gene)
APCMetabolite10077584 (PubChem-compound)
BCHEGeneProduct590 (Entrez Gene)
CES1GeneProduct1066 (Entrez Gene)
CES2GeneProduct8824 (Entrez Gene)
CYP3A4GeneProduct1576 (Entrez Gene)
CYP3A5GeneProduct1577 (Entrez Gene)
IrinotecanMetaboliteCHEBI:80630 (ChEBI)
M4Metabolitemolecular weight, 558
NPC1GeneProduct4864 (Entrez Gene)
SLCO1B1GeneProduct10599 (Entrez Gene)
SN-38MetaboliteCHEBI:8988 (ChEBI)
SN-38GMetaboliteCHEBI:8990 (ChEBI)
UGT1A10GeneProduct54575 (Entrez Gene)
UGT1A1GeneProduct54658 (Entrez Gene)
UGT1A9GeneProduct54600 (Entrez Gene)

Annotated Interactions

No annotated interactions

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