Abstract
Drug-induced liver injury (DILI) is one of the most serious and frequent drug-related adverse events in humans. Selenium (Se) and glutathione (GSH) have a crucial role for the hepatoprotective effect against reactive metabolites or oxidative damage leading to DILI. The hepatoprotective capacity related to Se and GSH in rodents is considered to be superior compared to the capacity in humans. Therefore, we hypothesize that Se/GSH-depleted rats could be a sensitive animal model to predict DILI in humans. In this study, Se-deficiency is induced by feeding a Se-deficient diet and GSH-deficiency is induced by l-buthionine-S,R-sulfoxinine treatment via drinking water. The usefulness of this animal model is validated using flutamide, which is known to cause DILI in humans but not in intact rats. In the Se/GSH-depleted rats from the present study, decreases in glutathione peroxidase-1 protein expression and GSH levels and an increase in malondialdehyde levels in the liver are observed without any increase in plasma liver function parameters. Five-day repeated dosing of flutamide at 150 mg/kg causes hepatotoxicity in the Se/GSH-depleted rats but not in normal rats. In conclusion, Se/GSH-depleted rats are the most sensitive for detecting flutamide-induced hepatotoxicity in all the reported animal models.
Highlights
Drug-induced liver injury (DILI) is one of the most serious and frequent drug-related adverse events in non-clinical toxicity studies or in clinical settings and a main reason for regulatory action pertaining to drugs, including stopping clinical trials or withdrawal from the marketplace [1,2]
Glutathione peroxidase (GPx)-1 is localized in cytosol and mitochondria and plays a significant role in the degeneration of hydrogen peroxide (H2O2) and fatty acid hydroperoxides, especially in mitochondria because mitochondria lack catalase, which is another enzyme degenerating HIn2t.OJ.2M[o7l.–S9c]i.. 2I0n19a, 1d8d, xition, peroxynitrite, which is a peroxide of nitrogen monoxide (NO), is a s2troofn1g0 inducer of oxidative stress and inflammatory reactions [10]
Plasma ALT, T-BIL, GgSlHu-tdamepaletteeddgerhoyudpr. ogenase (GLDH) and sorbitol dehydrogenase (SDH) levels were significantly increased in the Se/GSH-depleted (Se/GSH (−)) rats treated with flutamide when compared with the matched control group but not in intact (Se/GSH (+)) rats (Figure 4)
Summary
Drug-induced liver injury (DILI) is one of the most serious and frequent drug-related adverse events in non-clinical toxicity studies or in clinical settings and a main reason for regulatory action pertaining to drugs, including stopping clinical trials or withdrawal from the marketplace [1,2]. Plasma ALT, T-BIL, GLDH and SDH levels were significantly increased in the Se/GSH-depleted (Se/GSH (−)) rats treated with flutamide when compared with the matched control group but not in intact (Se/GSH (+)) rats (Figure 4). In combination with severe depletion of GSH by feeding an amino acid-deficient diet to CYP1A2 knockout mice, a high dose level of flutamide (400 mg/kg for 14 days) induced a mild increase in plasma ALT level and a slight increase in single cell necrosis in the liver [44]. Using γ-GCS knockdown rats, dosing flutamide at 100 mg/kg for seven days increased plasma AST and ALT levels, the increases were very slight and there were no histopathological findings suggestive of hepatotoxicity in the liver [45]. Se/GSH-depleted rats established in the present study are the most sensitive to the detection of the flutamide-induced hepatotoxicity in all the reported animal models
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