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Enhanced clearance of topoisomerase I inhibitors from human colon cancer cells by glucuronidation
- Source :
- Biochemical Pharmacology. 63:607-613
- Publication Year :
- 2002
- Publisher :
- Elsevier BV, 2002.
-
Abstract
- As part of a program to identify novel mechanisms of resistance to topoisomerase I (topo I) inhibitors, the cellular pharmacology of 7-ethyl-10-hydroxycamptothecin (SN-38), the active metabolite of clinically used irinotecan (CPT-11) and NU/ICRF 505, an anthraquinone-tyrosine conjugate, has been investigated in two human colorectal cancer (CRC) cell lines. Two novel metabolites of NU/ICRF 505 (M1 and M2) and a single metabolite of SN-38 (M1) were detected by high performance liquid chromatography in the culture medium of HT29 cells but were absent in HCT116 cells. Identities of all three metabolites were established by a combination of biochemical and physicochemical techniques. M1 of SN-38 was the C10-(beta)-glucuronide of the parent lactone while M1 of NU/ICRF 505 was the C4-O-glucuronide and M2 the tyrosine-O-glucuronide, both of the parent compound. Drug transport studies revealed that by 24hr HT29 cells had effectively cleared 82.5% of NU/ICRF 505 (10 microM) into the culture medium as the two glucuronides. In contrast, intracellular concentrations of NU/ICRF 505 were maintained in HCT116 cells in the absence of glucuronidation at a level 550 times greater than in HT29 cells. HT29 cells cleared 40.9% of SN-38 (1 microM) as the glucuronide to the culture medium, while the parent drug was maintained at a level 2-fold greater in HCT116 cells. Enhanced drug clearance due to glucuronidation may contribute to intrinsic drug resistance of human CRC.
- Subjects :
- Magnetic Resonance Spectroscopy
Metabolic Clearance Rate
Metabolite
Glucuronidation
Anthraquinones
Glucuronates
SN-38
Pharmacology
Irinotecan
Biochemistry
Mass Spectrometry
chemistry.chemical_compound
Glucuronides
Tumor Cells, Cultured
medicine
Humans
Enzyme Inhibitors
neoplasms
Active metabolite
biology
Chemistry
Topoisomerase
digestive system diseases
Cell culture
Colonic Neoplasms
biology.protein
Tyrosine
Camptothecin
Topoisomerase I Inhibitors
Glucuronide
HT29 Cells
medicine.drug
Subjects
Details
- ISSN :
- 00062952
- Volume :
- 63
- Database :
- OpenAIRE
- Journal :
- Biochemical Pharmacology
- Accession number :
- edsair.doi.dedup.....914e77674dc4f64597caea2854c3fa3c
- Full Text :
- https://doi.org/10.1016/s0006-2952(01)00812-7