Assessment of genotoxicity in rats treated with the antidiabetic agent, pioglitazone

Abstract

Pioglitazone (PIO), a member of the thiazolidinedione class of antidiabetic agents, specifically targets insulin resistance. Drugs of this class act as ligands for the gamma subtype of the peroxisome proliferator-activated receptor. Although troglitazone, another drug in this class, displayed unacceptable hepatotoxicity, PIO was approved for human use by the U.S. Food and Drug Administration. To our knowledge, there are no published reports on the genotoxicity of PIO; however, the package insert indicates that it has minimal genotoxicity. In this study, we used the comet assay to investigate the DNA damage in the peripheral blood and liver cells of rats treated with PIO. Sixteen male Sprague-Dawley rats were randomly distributed into four groups, and dosed daily for 14 days by oral gavage with 0, 10, 20, and 40 mg/kg/day PIO. A dose-dependent increase in DNA damage, as assessed by % tail DNA, was observed in both hepatocytes and blood lymphocytes of the PIO-treated groups, with significant increases detected between the rats treated with all the doses of PIO and the control, and between the rats treated with different PIO doses (P < 0.005 to P < 0.0001). Treating nuclei from the exposed animals with an enzyme cocktail containing Fpg and Endonuclease III prior to performing the comet assay increased the level of DNA damage, which reflects oxidized purine and pyrimidine. Taken together, our data indicate that PIO is able to dose-dependently induce DNA damage in both the liver and blood lymphocytes of rats, which is partially due to the generation of oxidative lesions.

Evaluation of vitamin B12 effects on DNA damage induced by pioglitazone

“…This is consistent with the previous studies, for example Bedir et al indicated that pioglitazone induces DNA damage in a dose-dependent manner in both liver cells and peripheral whole blood lymphocytes of rats [9].…”

“…In addition, pioglitazone was shown to reduce blood pressure, atherogenic dyslipidemia, microalbuminuria and visceral obesity [8]. Two studies showed that, pioglitazone can induce DNA damage to liver and blood cells [9]. This DNA damage is suggested to be the result of the generation of free radicals due to increased oxidative stress, resulting from the uncoupled cellular environment and cytochrome enzymes mediated oxidation reaction [10].…”

Peroxisome Proliferator Activator Receptor (PPAR)-γLigand, but Not PPAR-α, Ameliorates Cyclophosphamide-Induced Oxidative Stress and Inflammation in Rat Liver

“…Despite sporadic contradictory studies [20, 55], PIO has been reported to attenuate liver injury via recovering hepatic oxidant/antioxidant balance in several animal models, as it succeeded in repairing hepatic DNA damaged due to high fat diet in mice [56], abolishing hepatic oxidative stress in alloxan-induced diabetic rabbit [57], preventing lipopolysaccharide-induced liver injury [58], and recovering liver after ischemia/reperfusion in rats [23]. In humans, PIO was demonstrated to improve hepatic functional parameters in nonalcoholic fatty liver patients [59] and in nondiabetic patients suffering from metabolic syndrome [60].…”

Effect of Thiazolidinediones on the Erythropoeitic and Germinal Cells in the Male Wistar Rats

“…Enhancement in the oxidative stress due to generation of free radicals from the mitochondrial and/or extra mitochondrial sources was considered as the possible reason for the PIO mediated nuclear damage (Bedir et al 2008). However, several studies in the past have reported that TZDs posses potent anti-oxidant property.…”

“…However, a recent study reveals that PIO administration for 2 weeks (10–40 mg/kg/day) has enhanced the DNA damage in rat hepatocytes and blood lymphocytes (Bedir et al 2008). Similarly, in another study, RSG has shown increased nuclear damage in rat hepatocytes when it was tested daily (0.5–2.0 mg/kg) for two weeks (Bedir et al 2006).…”