Mechanism of paraquat toxicity in lung and its relevance to treatment.
The symptoms of paraquat poisoning depend largely on the amount of compound consumed, although in many cases the most characteristic feature of poisoning is lung damage, causing severe anoxia which leads to death. Studies in experimental animals have demonstrated that paraquat produces an acute damaging phase in the lung, followed by a reparative phase dominated by an extensive fibrosis. The latter is a major contributor to the lung lesion that causes anoxia. The specific toxicity in the lung can be explained in part by the selective accumulation of paraquat into this organ in comparison with other tissues. The accumulation is energy-dependent and probably specific to certain lung cells. It is now known that paraquat is accumulated into the lung by a recently described diamine transport process located in the alveolar epithelial cells and the Clara cells of the airways. When accumulated, paraquat undergoes a NADPH-dependent one-electron reduction to for its free radical which almost instantly reacts with molecular oxygen to reform the cation and concomitantly produce superoxide anion. This species of oxygen radical can contribute to the formation of more toxic species of radical which may directly damage vital cellular constituents. Paraquat has been shown to stimulate rapidly the pentose phosphate pathway and inhibit the synthesis of fatty acids in the lung in a dose-dependent manner. In addition there is a rapid increase in the pulmonary levels of mixed disulphides and the eventual reduction of NADPH levels in the lung. These results are consistent with the suggestion that paraquat causes a rapid and pronounced oxidation of NADPH which initiates compensatory biochemical responses in the lung.(ABSTRACT TRUNCATED AT 250 WORDS)
D000818:Animals; D007408:Intestinal Absorption; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009249:NADP / Q000378:metabolism; D010269:Paraquat / Q000378:metabolism / Q000633:toxicity*
D009249:NADP; D010269:Paraquat