N-nitroso metabolite of carbofuran induces apoptosis in CHL cells by cytochrome c-mediated activation of caspases.
Carbofuran is an anti-acetylcholinesterase insecticide regarded as a relatively safe chemical based on extensive toxicological data. However, the N-nitroso metabolite of carbofuran has been reported to be genotoxic. We previously observed that N-nitrosocarbofuran (NOCF) induces apoptosis and cell cycle arrest in Chinese hamster lung (CHL) fibroblasts. To extend our initial observations, we investigated the molecular mechanism of NOCF-induced apoptosis. Treatment of cells with NOCF caused dose-dependent upregulation of cytosolic factors, such as Bax and Bid, and release of cytochrome c, which were accompanied by activation of caspase-9. We also observed activation of caspase-8 and caspase-3, and subsequent cleavage of poly(ADP-ribose) polymerase. A broad-spectrum caspase inhibitor and a caspase-8-specific inhibitor completely blocked caspase-3 activation and cell death induced by NOCF. These results suggest that the mitochondrial pathway is primarily involved in the NOCF-induced apoptosis of CHL cells.
College of Pharmacy and Medicinal Resources Research Center, Wonkwang University, Jeonbuk 570-749, Republic of Korea.
Bang-Wool
BW
Lee
Seon-Hee
SH
Oh
Jin-Ho
JH
Chung
Chang-Kiu
CK
Moon
Byung-Hoon
BH
Lee
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D016466:CHO Cells; D002235:Carbofuran / Q000031:analogs & derivatives* / Q000633:toxicity*; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D006224:Cricetinae; D003412:Cricetulus; D045304:Cytochromes c / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D020287:In Situ Nick-End Labeling
D061945:Caspase Inhibitors; C445260:N-nitrosocarbofuran; D045304:Cytochromes c; D020169:Caspases; D002235:Carbofuran