Paraquat-induced oxidative stress and dysfunction of cellular redox systems including antioxidative defense enzymes glutathione peroxidase and thioredoxin reductase.
We examined if paraquat-induced oxidative stress and cytotoxicity in pulmonary microvascular endothelial cells are associated with cellular redox systems such as the glutathione system and the thioredoxin system. Loss of viability, accompanied by marked decreases in glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and thioredoxin reductase activities, occurred 48 h after exposure to 1mM paraquat. These changes were preceded by an increased production of hydrogen peroxide after the decrease in glutathione peroxidase activity. Glutaredoxin activity was not decreased even after exposure to paraquat for 48 h, whereas thioredoxin activity was slightly decreased at 48 h. Unexpectedly, the activity of peroxiredoxin, a non-selenoenzyme, was almost completely lost at 24h. Loss of GAPDH activity and viability was notably aggravated by mercaptosuccinate. Selenium supplementation suppressed the loss of activities of glutathione peroxidase and thioredoxin reductase and alleviated paraquat-induced cytotoxicity. An in vitro experiment demonstrated that GAPDH was highly susceptible to reactive oxygen species generated in the xanthine-xanthine oxidase system, whereas thioredoxin reductase was considerably resistant. Taken together, the results suggest that the reduced regenerative ability of oxidatively damaged proteins including GAPDH due to the inactivation of thioredoxin reductase and glutathione peroxidase by paraquat may contribute to increasing oxidative stress, leading to cell death.
Takizawa
Masashi
M
School of Pharmacy, Hokkaido Pharmaceutical University, Otaru, Hokkaido 047-0264, Japan.
Komori
Kumiko
K
Tampo
Yoshiko
Y
Yonaha
Masanori
M
D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D005979:Glutathione Peroxidase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D006540:Herbicides / Q000633:toxicity*; D006861:Hydrogen Peroxide / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D010269:Paraquat / Q000633:toxicity*; D010544:Peroxidases / Q000378:metabolism; D054464:Peroxiredoxins; D012643:Selenium / Q000494:pharmacology; D013552:Swine; D013870:Thiomalates / Q000494:pharmacology; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors / Q000378:metabolism*
D004338:Drug Combinations; D006540:Herbicides; D013870:Thiomalates; C046062:2-thiomalic acid; D006861:Hydrogen Peroxide; D010544:Peroxidases; D054464:Peroxiredoxins; D005979:Glutathione Peroxidase; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D013880:Thioredoxin-Disulfide Reductase; D012643:Selenium; D010269:Paraquat