Purpose: Carboxylesterase 2 (CES2) is involved in the activation of the anticancer drug irinotecan to its active metabolite SN-38. We previously identified a single nucleotide polymorphism (SNP), with an allele frequency around 10%, as possibly involved in enzyme expression (Clin Pharmacol Ther 76:528-535, 2004), which could explain the large individual variation in SN-38 disposition.
Methods: The 830C>G SNP, located in the 5' untranslated region of the gene, was analysed in various DNA samples extracted from: (1) the National Cancer Institute NCI-60 panel of human tumour cell lines; (2) a collection of 104 samples of normal tissue from colorectal cancer patients; (3) blood samples from a population of 95 normal subjects; (4) a collection of 285 human livers. CES2 genotypes were tentatively related to irinotecan cytotoxicity and CES2 expression in the NCI-60 panel; to response to treatment and event-free survival in colorectal cancer patients; and to CES2 expression and catalytic activity in subsets of the human liver collection.
Results: No significant relationship was found in the NCI-60 panel between CES2 830C>G genotype and irinotecan cytotoxicity or CES2 expression. No significant relationship was found between CES2 830C>G genotype and the toxicity and therapeutic efficacy (tumour response, event-free survival) of irinotecan in colorectal cancer patients. There was no significant relationship between CES2 830C>G genotype and CES2 expression and catalytic activity determined in a subset of genotype-selected liver samples.
Conclusion: The 830C>G SNP of CES2 is unlikely to have significant functional consequences on CES2 expression, activity or function.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1007/s00280-007-0493-9 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Protein abundance of drug transporters and drug-metabolizing enzymes in paired healthy and tumor tissue from colorectal cancer patients.
Int J Pharm
January 2025
Drug Delivery and Disposition, KU Leuven, Gasthuisberg ON2, Herestraat 49 - box 921, 3000 Leuven, Belgium. Electronic address:
The widespread prevalence of colorectal cancer and its high mortality rate emphasize the urgent need for more effective therapies. When developing new drug products, a key aspect is ensuring that sufficiently high concentrations of the active drug are reached at the site of action. Drug transporters and drug-metabolizing enzymes can significantly influence the absorption and local accumulation of drugs in intestinal tissue.
View Article and Find Full Text PDFNear-infrared fluorescence imaging tool with large Stokes shift for sensitively detecting carboxylesterase 2 and monitoring its expression in non-alcoholic fatty liver disease.
Talanta
April 2025
College of Chemistry, Jilin Province Research Center for Engineering and Technology of Spectral Analytical Instruments, Jilin University, Qianjin Street 2699, Changchun, 130012, China. Electronic address:
Non-alcoholic fatty liver disease (NAFLD) now affects more than one quarter of the global population and becomes a heavy public health burden. However, the underlying mechanism for the pathogenesis of NAFLD is still not clear. Carboxylesterase 2 (CES2), highly abundant in the liver and intestine, plays an important role in endogenous lipid metabolism and lipolysis.
View Article and Find Full Text PDFIntestinal human carboxylesterase 2 (CES2) expression rescues drug metabolism and most metabolic syndrome phenotypes in global Ces2 cluster knockout mice.
Acta Pharmacol Sin
November 2024
Division of Pharmacology, The Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands.
Article Synopsis
- - Carboxylesterase 2 (CES2) is primarily found in the liver and intestine, playing a significant role in metabolizing various compounds, influencing drug effectiveness, and affecting lipid and glucose metabolism.
- - The study involved creating knockout mice lacking CES2 genes and transgenic mice with human CES2 to assess the effects of CES2 on drug metabolism and metabolic health.
- - Findings revealed that while the absence of CES2 led to fatty liver and metabolic issues, introducing human CES2, especially in the intestine, improved these conditions and could potentially address metabolic syndrome challenges.
Generation and application of CES1-knockout Tet-Off-regulated CYP3A4 and UGT1A1-expressing Caco-2 cells.
Toxicol Lett
November 2024
Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan; Laboratory of Biochemistry and Molecular Biology, School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan; Laboratory of Functional Organoid for Drug Discovery, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka 567-0085, Japan; Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Osaka, Japan; Global Center for Medical Engineering and Informatics, Osaka University, Osaka 565-0871, Japan; Center for Infectious Disease Education and Research (CiDER), Osaka University, Osaka 565-0871, Japan. Electronic address:
Caco-2 cells, a human colorectal adenocarcinoma cell line, are widely used to model small intestinal epithelial cells in the drug development process because they can predict drug absorption with high accuracy. However, Caco-2 cells have several issues. First, Caco-2 cells have little expression of cytochrome P450 3A4 (CYP3A4), which is a major drug-metabolizing enzyme in the human intestine.
View Article and Find Full Text PDFSex differences in the metabolic activation of and platelet response to vicagrel in mice: Androgen as a key player.
Biochem Pharmacol
December 2024
Division of Clinical Pharmacology, General Clinical Research Center, Nanjing First Hospital, China Pharmaceutical University, Nanjing 210006, China; Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China; Division of Clinical Pharmacology, General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China. Electronic address:
As a biological variable, sex influences the metabolism of and/or response to certain drugs. Vicagrel is being developed as an investigational new drug in China; however, it is unknown whether sex could affect its metabolic activation and platelet responsiveness. This study aimed to determine whether such differences could exist, and to elucidate the mechanisms involved.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!