Document Detail

Glutathione oxidation and mitochondrial depolarization as mechanisms of nordihydroguaiaretic acid-induced apoptosis in lipoxygenase-deficient FL5.12 cells.
MedLine Citation:
PMID:  10653524     Owner:  NLM     Status:  MEDLINE    
Nordihydroguaiaretic acid (NDGA) induces apoptosis in a variety of cell lines. The mechanism(s) of this effect is not known, although the focus has been on the ability of NDGA to inhibit lipoxygenase (LOX) activities. In the present study, NDGA-induced apoptosis was studied in a murine hematopoietic cell line, FL5.12. Although this cell line lacks detectable LOX protein or activities, NDGA (10 microM) was able to induce apoptosis. There was a massive loss of mitochondrial membrane potential by 4 h after the addition of NDGA, suggesting that this organelle might be targeted by NDGA. A pro-oxidant NDGA effect has been suggested as playing a role in apoptosis. This was supported by the findings that glutathione disulfide levels were increased by 4 h following treatment with 10 microM NDGA, that pretreatment with N-acetylcysteine completely blocked the NDGA-induced loss of membrane potential and apoptosis, and that lipid peroxidation was enhanced in cells treated with NDGA. However, no evidence of increased levels of reactive oxygen could be seen in NDGA-treated cells loaded with dichlorofluorescin diacetate or dihydrorhodamine and analyzed by flow cytometry. Bcl-X(L) protein levels were unaffected by NDGA treatment. Caspase-3 was rapidly activated with a peak at 8 h after FL5.12 cells were treated with NDGA. Ac-DEVD-CHO (25 microM) and boc-asp-FMK (20 microM) both inhibited caspase-3 enzyme activity by 97% 8 h after NDGA treatment. Boc-asp-FMK, a more general caspase inhibitor, delayed NDGA-induced apoptosis while Ac-DEVD-CHO, a more specific inhibitor of caspase-3, had no effect. These results suggest that NDGA-induced apoptosis happens through reactions that depolarize mitochondria, oxidize glutathione and lipids, but do not generate significant amounts of free reactive oxygen species.
S S Biswal; K Datta; S D Shaw; X Feng; J D Robertson; J P Kehrer
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Toxicological sciences : an official journal of the Society of Toxicology     Volume:  53     ISSN:  1096-6080     ISO Abbreviation:  Toxicol. Sci.     Publication Date:  2000 Jan 
Date Detail:
Created Date:  2000-02-15     Completed Date:  2000-02-15     Revised Date:  2010-09-17    
Medline Journal Info:
Nlm Unique ID:  9805461     Medline TA:  Toxicol Sci     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  77-83     Citation Subset:  IM    
Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, 78712-1074, USA.
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MeSH Terms
Acetylcysteine / pharmacology
Amino Acid Chloromethyl Ketones / pharmacology
Apoptosis / drug effects*
B-Lymphocytes / drug effects*,  enzymology
Blotting, Western
Caspase 3
Caspases / antagonists & inhibitors,  metabolism
Cell Line
Enzyme-Linked Immunosorbent Assay
Glutathione / metabolism*
Lipoxygenase / deficiency*
Lipoxygenase Inhibitors / pharmacology*
Membrane Potentials / drug effects,  physiology
Mitochondria / metabolism*
Nordihydroguaiaretic Acid / pharmacology*
Oligopeptides / pharmacology
Proto-Oncogene Proteins c-bcl-2 / metabolism
bcl-X Protein
Grant Support
Reg. No./Substance:
0/Amino Acid Chloromethyl Ketones; 0/Bcl2l1 protein, mouse; 0/Lipoxygenase Inhibitors; 0/Oligopeptides; 0/Proto-Oncogene Proteins c-bcl-2; 0/acetyl-aspartyl-glutamyl-valyl-aspartal; 0/bcl-X Protein; 0/butyloxycarbonyl-O-methyl-aspartyl-fluoromethyl ketone; 500-38-9/Nordihydroguaiaretic Acid; 616-91-1/Acetylcysteine; 70-18-8/Glutathione; EC; EC 3.4.22.-/Casp3 protein, mouse; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspases

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