Enhanced clearance of topoisomerase I inhibitors from human colon cancer cells by glucuronidation

Biochem Pharmacol. 2002 Feb 15;63(4):607-13. doi: 10.1016/s0006-2952(01)00812-7.


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.

MeSH terms

  • Anthraquinones / metabolism
  • Anthraquinones / pharmacokinetics*
  • Camptothecin / analogs & derivatives
  • Camptothecin / metabolism
  • Camptothecin / pharmacokinetics*
  • Colonic Neoplasms / metabolism*
  • Colonic Neoplasms / pathology
  • Enzyme Inhibitors / pharmacokinetics*
  • Glucuronates / metabolism
  • Glucuronides / pharmacokinetics*
  • HT29 Cells
  • Humans
  • Irinotecan
  • Magnetic Resonance Spectroscopy
  • Mass Spectrometry
  • Metabolic Clearance Rate
  • Topoisomerase I Inhibitors*
  • Tumor Cells, Cultured
  • Tyrosine / analogs & derivatives*
  • Tyrosine / metabolism
  • Tyrosine / pharmacokinetics*


  • 7-ethyl-10-hydroxycamptothecin glucuronide
  • Anthraquinones
  • Enzyme Inhibitors
  • Glucuronates
  • Glucuronides
  • NU-ICRF 505
  • Topoisomerase I Inhibitors
  • Tyrosine
  • Irinotecan
  • Camptothecin