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Oxidative Medicine and Cellular Longevity
Volume 2014 (2014), Article ID 398285, 9 pages
http://dx.doi.org/10.1155/2014/398285
Research Article

Flutamide-Induced Cytotoxicity and Oxidative Stress in an In Vitro Rat Hepatocyte System

1Department of Pharmacology & Toxicology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada M5S 1A8
2Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada M5S 3M2

Received 27 May 2014; Revised 1 September 2014; Accepted 20 September 2014; Published 13 October 2014

Academic Editor: Jing Yi

Copyright © 2014 Abdullah Al Maruf and Peter O’Brien. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Flutamide (FLU) is a competitive antagonist of the androgen receptor which has been reported to induce severe liver injury in some patients. Several experimental models suggested that an episode of inflammation during drug treatment predisposes animals to tissue injury. The molecular cytotoxic mechanisms of FLU in isolated rat hepatocytes using an in vitro oxidative stress inflammation system were investigated in this study. When a nontoxic hydrogen peroxide (H2O2) generating system (glucose/glucose oxidase) with peroxidase or iron(II) [Fe(II)] (to partly simulate in vivo inflammation) was added to the hepatocytes prior to the addition of FLU, increases in FLU-induced cytotoxicity and lipid peroxidation (LPO) were observed that were decreased by 6-N-propyl-2-thiouracil or deferoxamine, respectively. N-Acetylcysteine decreased FLU-induced cytotoxicity in this system. Potent antioxidants, for example, Trolox ((±)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid), resveratrol (3,5,4′-trihydroxy-trans-stilbene), and DPPD (N,N′-diphenyl-1,4-phenylenediamine) also significantly decreased FLU-induced cytotoxicity and LPO and increased mitochondrial membrane potential (MMP) and glutathione (GSH) levels in the H2O2 generating system with peroxidase. TEMPOL (4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl), a known reactive oxygen species (ROS) scavenger and superoxide dismutase mimetic, also significantly decreased toxicity caused by FLU in this system. These results raise the possibility that the presence or absence of inflammation may be another susceptibility factor for drug-induced hepatotoxicity.