Genotoxicity of acyl glucuronide metabolites formed from clofibric acid and gemfibrozil: a novel role for phase-II-mediated bioactivation in the hepatocarcinogenicity of the parent aglycones?

Toxicology and Applied Pharmacology
B C SallustioPhilip C Burcham

Abstract

Glucuronides formed from carboxylate-containing xenobiotics are more chemically reactive than most Phase II conjugates. However, while they have been shown to form protein adducts, their reactions with DNA have received little attention. We thus used the M13 forward mutational assay to assess the genotoxicity of acyl glucuronides formed from two widely used fibrate hypolipidemics, clofibric acid and gemfibrozil. Single-stranded M13mp19 bacteriophage DNA was incubated in pH 7.4 buffer for 16 h in the presence of 0, 1, 2.5, and 5 mM concentrations of each glucuronide as well as the respective aglycones. The modified DNA was then transfected into SOS-induced competent Escherichia coli JM105 cells and the transfection efficiency was determined after phage growth overnight at 37 degrees C. Significantly, both acyl glucuronides, but not the aglycones, caused a concentration-dependent decrease in the transfection efficiency of the DNA, with a greater than 80% decrease in phage survival produced by the 5 mM concentrations of the glucuronides. No increase in lacZa mutations accompanied the loss of phage survival. We propose that these genotoxic effects involve reactions with nucleophilic centers in DNA via a Schiff base mechanism that i...Continue Reading

Citations

Jul 16, 2005·Journal of Toxicology and Environmental Health. Part a·Andrew R HumpageIan R Falconer
Sep 18, 2015·Molecular Pharmaceutics·Emi KimotoManthena V S Varma
Jan 24, 2014·Oxidative Medicine and Cellular Longevity·Wai-Leng LeeLie-Fen Shyur
Mar 14, 2017·Toxicology Letters·Terry R Van VleetEric A G Blomme
Aug 25, 2007·Toxicology in Vitro : an International Journal Published in Association with BIBRA·Walter M A Westerink, Willem G E J Schoonen
Feb 27, 2007·Environment International·Marina IsidoriAlfredo Parrella
Dec 27, 2016·Drug Metabolism and Pharmacokinetics·Atsushi IwamuraTsuyoshi Yokoi
May 22, 2002·Therapeutic Drug Monitoring·Maria ShipkovaUNKNOWN German Study Group on Mycophenolate Mofetil Therapy in Pediatric Renal Transplant Recipients
Jan 28, 2003·Therapeutic Drug Monitoring·Maria ShipkovaEberhard Wieland
Nov 4, 2004·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Jane R KennyB Kevin Park
Jan 29, 2021·Analytical Methods : Advancing Methods and Applications·Dylan O'FlynnBlánaid White
Apr 11, 2003·Chemico-biological Interactions·Mark J Bailey, Ronald G Dickinson
Sep 10, 2019·Chemical Research in Toxicology·Hiroshi HaradaHiroo Takeda
Oct 28, 2021·Chemical Research in Toxicology·Chikako ShibazakiTomoyuki Ohe

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