Depletion of intracellular glutathione mediates butenolide-induced cytotoxicity in HepG2 cells.
Butenolide, 4-acetamido-4-hydroxy-2-butenoic acid gamma-lactone is one of the mycotoxins produced by Fusarium species which are often found on cereal grains and animal feeds throughout the world. It has been implicated as the etiology of some diseases both in animals and in humans. Though butenolide represents a potential threat to animal and human heath, there are few studies on its toxicity so far, especially on the toxic mechanisms. In this study, we investigated the cytotoxicity of butenolide on HepG2 cells and its possible mechanism from the viewpoint of oxidative stress. Butenolide reduced cell viability in a concentration- and time-dependent manner. A rapid depletion of intracellular glutathione (GSH) was observed after exposure cells to butenolide, concomitantly an increase in intracellular reactive oxygen species (ROS) production prior to cell death, indicating that oxidative stress was involved in butenolide cytotoxicity. To elucidate the role of GSH in the cytotoxicity of butenolide, intracellular GSH content was modulated before exposure to butenolide. l-buthionine-[S,R]-sulfoximine (BSO), a well-known inhibitor of GSH synthesis, aggravated butenolide-induced GSH depletion, ROS production and the loss in cell viability; in contrast, GSH depletion and ROS production was strongly inhibited, and the loss in cell viability was completely abrogated by thiol-containing compounds GSH, N-acetylcysteine (NAC) and dithiothreitol (DTT). Furthermore, a ROS scavenger catalase obviously abated ROS production and cytotoxicity induced by butenolide. Together, these results clearly demonstrate that oxidative stress plays an important role in butenolide cytotoxicity, and intracellular GSH depletion may be an original trigger of the onset of butenolide cytotoxicity.
Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
Yi-Mei
YM
Wang
Shuang-Qing
SQ
Peng
Qi
Q
Zhou
Min-Wei
MW
Wang
Chang-Hui
CH
Yan
Hai-Ying
HY
Yang
Guo-Qiang
GQ
Wang
D000081:Acetamides / Q000633:toxicity*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D016166:Free Radical Scavengers / Q000494:pharmacology; D005663:Furans / Q000633:toxicity*; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D009183:Mycotoxins / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000494:pharmacology; D013997:Time Factors
C511703:5-acetamido-2(5)-furanone; D000081:Acetamides; D016166:Free Radical Scavengers; D005663:Furans; D009183:Mycotoxins; D017382:Reactive Oxygen Species; D013438:Sulfhydryl Compounds; D005978:Glutathione