Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/22788
Citations
Scopus Web of ScienceĀ® Altmetric
?
?
Type: Journal article
Title: Bioactivation of carboxylic acid compounds by UDP-glucuronosyltransferases to DNA-damaging intermediates: Role of glycoxidation and oxidative stress in genotoxicity
Author: Sallustio, B.
DeGraaf, Y.
Weekley, J.
Burcham, P.
Citation: Chemical Research in Toxicology, 2006; 19(5):683-691
Publisher: Amer Chemical Soc
Issue Date: 2006
ISSN: 0893-228X
1520-5010
Statement of
Responsibility: 
Sallustio, Benedetta C ; Degraaf, Yvette C ; Weekley, Josephine S ; Burcham, Philip C
Abstract: Nonenzymatic modification of proteins by acyl glucuronides is well documented; however, little is known about their potential to damage DNA. We have previously reported that clofibric acid undergoes glucuronidation-dependent bioactivation to DNA-damaging species in cultured mouse hepatocytes. The aim of this study was to investigate the mechanisms underlying such DNA damage, and to screen chemically diverse carboxylic acid drugs for their DNA-damaging potential in glucuronidation proficient murine hepatocytes. Cells were incubated with each aglycone for 18 h, followed by assessment of compound cytotoxicity using the MTT assay and evaluation of DNA damage using the Comet assay. Relative cytotoxic potencies were ketoprofen > diclofenac, benoxaprofen, nafenopin >> gemfibrozil, probenecid > bezafibrate > clofibric acid. At a noncytotoxic (0.1 mM) concentration, only benoxaprofen, nafenopin, clofibric acid, and probenecid significantly increased Comet moments (P < 0.05 Kruskal-Wallis). Clofibric acid and probenecid exhibited the greatest DNA-damaging potency, producing significant DNA damage at 0.01 mM concentrations. The two drugs produced maximal increases in Comet moment of 4.51 x and 2.57 x control, respectively. The glucuronidation inhibitor borneol (1 mM) abolished the induction of DNA damage by 0.5 mM concentrations of clofibric acid and probenecid. In an in vitro cell-free system, clofibric acid glucuronide was 10 x more potent than glucuronic acid in causing DNA strand-nicking, although both compounds showed similar rates of autoxidation to generate hydroxyl radicals. In cultured hepatocytes, the glycation inhibitor, aminoguanidine, and the iron chelator, desferrioxamine mesylate, inhibited DNA damage by clofibric acid, whereas the free radical scavengers Trolox and butylated hydroxytoluene, and the superoxide dismutase mimetic bis-3,5-diisopropylsalicylate had no effect. In conclusion, clinically relevant concentrations of two structurally unrelated carboxylic acids, probenecid and clofibric acid, induced DNA damage in isolated hepatocytes via glucuronidation- dependent pathways. These findings suggest acyl glucuronides are able to access and damage nuclear DNA via iron-catalyzed glycation/glycoxidative processes.
Keywords: Hepatocytes; Animals; Mice; DNA Damage; Hydroxyl Radical; Guanidines; Carboxylic Acids; Glucuronides; Glucuronosyltransferase; Antioxidants; Comet Assay; Cell Survival; Oxidative Stress; Male
RMID: 0020060541
DOI: 10.1021/tx060022k
Appears in Collections:Pharmacology publications

Files in This Item:
There are no files associated with this item.


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.