Abstract
Paraquat (PQ) is a herbicide that preferentially accumulates in the lung and exerts its cytotoxicity via the generation of reactive oxygen species (ROS). There is no specific treatment for paraquat poisoning. Attempts have been made to increase the antioxidant status in the lung using antioxidants (e.g., superoxide dismutase, vitamin E, N-acetylcysteine) but the outcome from such treatments is limited. Encapsulation of antioxidants in liposomes improves their therapeutic potential against oxidant-induced lung damage because liposomes facilitate intracellular delivery and prolong the retention of entrapped agents inside the cell. In the present study, we compared the effectiveness of conventional N-acetylcysteine (NAC) and liposomal-NAC (L-NAC) against PQ-induced cytotoxicity and examined the mechanism(s) by which these antioxidant formulations conferred cytoprotection. The effects of NAC or L-NAC against PQ-induced cytotoxicity in A549 cells were assessed by measuring cellular PQ uptake, intracellular glutathione content, ROS levels, mitochondrial membrane potential, cellular gene expression, inflammatory cytokine release and cell viability. Pretreatment of cells with L-NAC was significantly more effective than pretreatment with the conventional drug in reducing PQ-induced cytotoxicity, as indicated by the biomarkers used in this study. Our results suggested that the delivery of NAC as a liposomal formulation improves its effectiveness in counteracting PQ-induced cytotoxicity.
Highlights
Paraquat (PQ) is a herbicide that preferentially accumulates in the lung and exerts its cytotoxic effects via the generation of reactive oxygen species (ROS) [1,2,3]
Challenge of A549 cells with NAC at concentrations ranging from 0 to 10 mM did not have any effect on cell viability 24 h after NAC exposure
Treatment of A549 cells with conventional NAC resulted in increased NAC uptake up to 2 h posttreatment; thereafter, levels remained unchanged up to 24 h posttreatment
Summary
Paraquat (PQ) is a herbicide that preferentially accumulates in the lung and exerts its cytotoxic effects via the generation of reactive oxygen species (ROS) [1,2,3]. Many studies have focused on increasing the antioxidant status in the lung to protect against PQ injury using various antioxidants, including antioxidant enzymes (e.g., SOD), vitamins (e.g., ascorbic acid, α-tocopherol), and low-molecular-weight thiol-containing antioxidants (e.g., glutathione (GSH), Nacetylcysteine (NAC)) but the outcomes from such treatments are limited or without success [2,3,4,5,6,7,8,9,10,11] The failure of these antioxidants to seriously modify the toxicity of the herbicide has been attributed mostly to their inability to cross cell membrane barriers and/or to their rapid clearance from cells [3, 4, 6, 7, 10, 11]. The relative ease in incorporating hydrophilic and lipophilic therapeutic agents into liposomes, the possibility of directly delivering liposomes to an accessible body site, such as the lung, and the relative nonimmunogenicity and low toxicity of liposomes have rendered the liposomal system highly attractive for drug delivery [3, 12, 16]
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