Cell death by 1-chloro-2,4-dinitrobenzene, an inhibitor of thioredoxin reductase and its dual regulation by nitric oxide in rats.
Thioredoxin (Trx), the oxidized form of which is converted to a reduced form by Trx reductase, regulates cell proliferation and survival. We investigated the effect of 1-chloro-2,4-dinitrobenzene (DNCB), an inhibitor of Trx reductase, on cell death in neuronal PC12 cells and rat glial cells. In both types of cells, culture with DNCB for 4 h stimulated lactate dehydrogenase (LDH) leakage. LDH leakage by DNCB was inhibited by an inhibitor of caspases. Addition of 2,2-(hydroxynitrosohydrazino)bis-ethanamine, of which 50% decays and releases nitric oxide (NO) in 21 h, inhibited DNCB-induced LDH leakage. Addition of 10 microM N-ethyl-2-(1-ethyl-2-hydroxy-2-nitrosohydrazino)-ethanamine (NOC-12), of which 50% decays and releases NO in 100 min, inhibited DNCB-induced LDH leakage, although 0.2 mM NOC-12 enhanced the leakage in PC12 cells. These findings suggest that DNCB induces cell death of neuronal and glial cells accompanied by caspase(s) activation. NO inhibits DNCB-induced cell death in both types of cells, although excess NO showed a toxic effect.
Ishikawa
A
A
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Kubota
Y
Y
Murayama
T
T
Nomura
Y
Y
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004137:Dinitrochlorobenzene / Q000494:pharmacology*; D007770:L-Lactate Dehydrogenase / Q000187:drug effects* / Q000378:metabolism; D009457:Neuroglia / Q000187:drug effects*; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D016716:PC12 Cells; D051381:Rats; D017208:Rats, Wistar; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors*
D000590:Amino Acid Chloromethyl Ketones; D015853:Cysteine Proteinase Inhibitors; D004137:Dinitrochlorobenzene; D020030:Nitric Oxide Donors; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D009569:Nitric Oxide; D007770:L-Lactate Dehydrogenase; D013880:Thioredoxin-Disulfide Reductase