Abstract
Carbon tetrachloride (CCl4) is routinely used as a model compound for eliciting centrilobular hepatotoxicity. It can be bioactivated to the trichloromethyl radical, which causes extensive lipid peroxidation and ultimately cell death by necrosis. Overactivation of poly(ADP-ribose) polymerase-1 (PARP-1) can rapidly reduce the levels of β-nicotinamide adenine dinucleotide and adenosine triphosphate and ultimately promote necrosis. The aim of this study was to determine whether inhibition of PARP-1 could decrease CCl4-induced hepatotoxicity, as measured by degree of poly(ADP-ribosyl)ation, serum levels of lactate dehydrogenase (LDH), lipid peroxidation, and oxidative DNA damage. For this purpose, male ICR mice were administered intraperitoneally a hepatotoxic dose of CCl4 with or without 6(5H)-phenanthridinone, a potent inhibitor of PARP-1. Animals treated with CCl4 exhibited extensive poly(ADP-ribosyl)ation in centrilobular hepatocytes, elevated serum levels of LDH, and increased lipid peroxidation. In contrast, animals treated concomitantly with CCl4 and 6(5H)-phenanthridinone showed significantly lower levels of poly(ADP-ribosyl)ation, serum LDH, and lipid peroxidation. No changes were observed in the levels of oxidative DNA damage regardless of treatment. These results demonstrated that the hepatotoxicity of CCl4 is dependent on the overactivation of PARP-1 and that inhibition of this enzyme attenuates the hepatotoxicity of CCl4.
Highlights
Many pathological conditions are induced by chemical exposures, of which an increase in free radical production has been shown to be a primary and ubiquitous event in producing toxicity[1]
Oxidative stress or chemical insults that are capable of generating DNA strand breaks cause a remarkable increase in poly(ADP-ribose) polymerase-1 (PARP-1; EC 2.4.2.30) activity[2], whose activity is barely detectable under normal cellular conditions
Protective effects of PARP-1 inhibitor against CCl4-induced damage of hepatocytes Serum lactate dehydrogenase (LDH) activity confirmed the protective effects of 6(5H)-phenanthridinone against CCl4-induced tissue damage and the lack of effect of dimethyl sulfoxide (DMSO) and 6(5H)phenanthridinone administered alone (Figure 1)
Summary
Many pathological conditions are induced by chemical exposures, of which an increase in free radical production has been shown to be a primary and ubiquitous event in producing toxicity[1]. Oxidative stress or chemical insults that are capable of generating DNA strand breaks cause a remarkable increase in poly(ADP-ribose) polymerase-1 (PARP-1; EC 2.4.2.30) activity[2], whose activity is barely detectable under normal cellular conditions. When DNA damage is moderate, PARP-1 works for its repair. PARP-1 catalyzes the transfer of ADP-ribose moieties to acceptor sites on itself, a process called “automodification”[3,4]. This automodification leads to the release of PARP-1 from DNA strand termini, due to the negative charge repulsion between poly(ADP-ribose) and DNA, and allows for other proteins of the DNA excision repair pathways to access and work at sites of damage
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