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Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear enzyme involved in the detection of DNA strand termini. Extensive cellular damage can overactivate PARP-1, which rapidly depletes the cellular stores of NAD+ and ATP, resulting in necrotic cell death. The purpose of the present study was to determine whether 6(5H)-phenanthridinone, a potent inhibitor of PARP-1, could attenuate the hepatotoxicity of carbon tetrachloride (CCl4). Male ICR mice treated via the intraperitoneal route with CCl4 exhibited severe necrotic centrilobular lesions and significantly elevated serum transaminases. In contrast, the histopathology and serum biochemistry of animals treated concomitantly with CCl4 and 6(5H)-phenanthridinone were not significantly different versus controls. In conclusion, the results of this study demonstrate that the hepatotoxicity of CCl4 can be blocked independently of its metabolism and suggest the predominant role of PARP-1 overactivation in chemical-induced toxicity.

Overactivation of poly(ADP-ribose) polymerase-1 (PARP-1) in response to oxidative stress has been shown to contribute to necrotic cell death by consuming NAD+ and ATP. In the present study, PARP-1 overactivation was determined by identifying the distribution and accumulation of poly(ADP-ribose) following intraperitoneal administration of a hepatotoxic dose of carbon tetrachloride (572 mg/kg). Treated animals exhibited lipid peroxide levels 16.5-fold higher than controls. Serum activities of glutamic pyruvic transaminase and glutamic oxaloacetic transaminase were increased by 6.1-fold and 22.8-fold, respectively. Lactate dehydrogenase activity was significantly increased by 1.2-fold. Histopathological analyses revealed severe necrosis and increased poly(ADP-ribsyl)ation of cells in the centrilobular region of treated animals versus saline controls. These results demonstrate the role of PARP-1 overactivation in chemical-induced pathologies and suggest the potential role of PARP-1 inhibitors at preventing toxicity.

Stimulation of alpha-adrenergic receptors by cold stress or adrenergic agents has been shown to potentiate the toxicity of numerous toxicants. Several lines of evidence indicate that this interaction is dependent on glutathione depression and increased cytosolic Ca2+ concentrations produced by alpha1-adrenergic compounds. In this report, evidence is provided in support of the mechanism of adrenoreceptor-mediated potentiation of nephrotoxicity. Alpha1-adrenergic agonists are shown to potentiate the toxicity of nephrotoxicants that exert their toxic effects via glutathione conjugation or Ca2+ deregulation. This review summarizes the effects of the alpha1-adrenergic agonist, phenylephrine, at enhancing the toxicity of 2-bromohydroquinone, 1,2-dibromoethane, and cis-diammineplatinum(II) dichloride.

The lung has been shown to be a target organ for the deleterious effects of Benzo[a]pyrene (B[a]P), regardless of the route of exposure. 8-hydroxy-2'-deoxyguanosine (oxo8dG) is a mutagenic lesion formed in DNA following exposure to B[a]P. The objective of this study was to determine the capacity of different organs to repair oxo8dG following intraperitoneal (i.p.) treatment with B[a]P. Male Spraque-Dawley rats were administered 20 mg/kg B[a]P i.p., 2 times/day for 5 days. A 26% decrease in the capacity to remove oxo8dG was observed in lung tissue at 72 hours and recovered 20% above control values at 120 hours. The capacity of the liver and kidney remained at baseline for all time points analyzed. A 7-fold increase in oxo8dG was observed in the lung at 72 hours. This study demonstrates that organ-specific differences exist in the capacity to remove oxo8dG and further demonstrates the susceptibility of lung tissue to the effects of B[a]P.