Cytotoxicity induced by grape seed proanthocyanidins: role of nitric oxide.
Grape seed proanthocyanidin extract (GPSE) at high doses has been shown to exhibit cytotoxicity that is associated with increased apoptotic cell death. Nitric oxide (NO), being a regulator of apoptosis, can be increased in production by the administration of GSPE. In a chick cardiomyocyte study, we demonstrated that high-dose (500 microg/ml) GSPE produces a significantly high level of NO that contributes to increased apoptotic cell death detected by propidium iodide and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining. It is also associated with the depletion of intracellular glutathione (GSH), probably due to increased consumption by NO with the formation of S-nitrosoglutathione. Co-treatment with L-NAME, a NO synthase inhibitor, results in reduction of NO and apoptotic cell death. The decline in reduced GSH/oxidized GSH (GSSG) ratio is also reversed. N-Acetylcysteine, a thiol compound that reacts directly with NO, can reduce the increased NO generation and reverse the decreased GSH/GSSG ratio, thereby attenuating the cytotoxicity induced by high-dose GSPE. Taken together, these results suggest that endogenous NO synthase (NOS) activation and excessive NO production play a key role in the pathogenesis of high-dose GSPE-induced cytotoxicity.
Emergency Resuscitation Center, Section of Emergency Medicine, Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
Z H
ZH
Shao
C W
CW
Hsu
W T
WT
Chang
G B
GB
Waypa
J
J
Li
D
D
Li
C Q
CQ
Li
T
T
Anderson
Y
Y
Qin
P T
PT
Schumacker
L B
LB
Becker
T L Vanden
TL
Hoek
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D016923:Cell Death; D002470:Cell Survival; D002478:Cells, Cultured; D002642:Chick Embryo; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005978:Glutathione / Q000378:metabolism; D056604:Grape Seed Extract; D032383:Myocytes, Cardiac / Q000187:drug effects*; D009569:Nitric Oxide / Q000502:physiology*; D010936:Plant Extracts / Q000633:toxicity*; D044945:Proanthocyanidins / Q000633:toxicity*
D056604:Grape Seed Extract; C511402:Grape Seed Proanthocyanidins; D010936:Plant Extracts; D044945:Proanthocyanidins; D009569:Nitric Oxide; D005978:Glutathione; D000111:Acetylcysteine