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Pathway Description
Irinotecan Topoisomerase Inhibitor Action Pathway
Homo sapiens
Category:
Metabolite Pathway
Sub-Category:
Drug Action
Created: 2021-05-07
Last Updated: 2023-10-25
Irinotecan is a semi-synthetic analogue of camptothecin which is a topoisomerase IB inhibitor. It is used to treat colorectal cancer. It's mechanism of action against topoisomerase I is that it forms a tertiary complex between the DNA and the topoisomerase I enzyme causing double strand breaks. It first has to be metabolized by liver carboxylesterase 1 into SN-38, which is the active metabolite that inhibits topoisomerase. SN-38 can be inactivated by UGT1A1 into SN-38 glucuronide which upregulated in some individuals leading to irinotecan resistance. Individuals might also have a reduced function variant of UGT1A1 which can lead to increased metabolism of irinotecan and leads to irinotecan toxicity. Toxicity of irinotecan leads to gastrointestinal complications as well as nausea, vomiting and headaches. Irinotecan is administered usually intravenously as a solution.
References
Irinotecan Topoisomerase Inhibitor Pathway References
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Pubmed: 1918003
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Shibata F, Takagi Y, Kitajima M, Kuroda T, Omura T: Molecular cloning and characterization of a human carboxylesterase gene. Genomics. 1993 Jul;17(1):76-82. doi: 10.1006/geno.1993.1285.
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Levesque E, Girard H, Journault K, Lepine J, Guillemette C: Regulation of the UGT1A1 bilirubin-conjugating pathway: role of a new splicing event at the UGT1A locus. Hepatology. 2007 Jan;45(1):128-38. doi: 10.1002/hep.21464.
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Ritter JK, Crawford JM, Owens IS: Cloning of two human liver bilirubin UDP-glucuronosyltransferase cDNAs with expression in COS-1 cells. J Biol Chem. 1991 Jan 15;266(2):1043-7.
Pubmed: 1898728
Ritter JK, Chen F, Sheen YY, Tran HM, Kimura S, Yeatman MT, Owens IS: A novel complex locus UGT1 encodes human bilirubin, phenol, and other UDP-glucuronosyltransferase isozymes with identical carboxyl termini. J Biol Chem. 1992 Feb 15;267(5):3257-61.
Pubmed: 1339448
Nagase T, Ishikawa K, Nakajima D, Ohira M, Seki N, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O: Prediction of the coding sequences of unidentified human genes. VII. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro. DNA Res. 1997 Apr 28;4(2):141-50. doi: 10.1093/dnares/4.2.141.
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Nakajima D, Okazaki N, Yamakawa H, Kikuno R, Ohara O, Nagase T: Construction of expression-ready cDNA clones for KIAA genes: manual curation of 330 KIAA cDNA clones. DNA Res. 2002 Jun 30;9(3):99-106. doi: 10.1093/dnares/9.3.99.
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Pubmed: 15164053
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