title: Grape seed proanthocyanidins induce pro-oxidant toxicity in cardiomyocytes.
abstract: Grape seed proanthocyanidin extract (GSPE), a polyphenolic compound with antioxidant properties, may protect against cardiac ischemia and reperfusion injury. However, its potential toxicity at higher doses is unknown. The authors tested the effects of GSPE on reactive oxygen species (ROS) generation, cell survival, lactate dehydrogenase (LDH) release, and caspase- 3 activity using chick cardiomyocytes incubated with GSPE at 5, 10, 50, 100, or 500 micrograms/mL in medium for 8 h. Exposure to increasing concentrations of GSPE (100 or 500 micrograms/mL) resulted in an increase in ROS generation and cell death as measured by propidium iodide uptake and LDH release. Caspase-3 activity was significantly increased fourfold in cells exposed to GSPE 500 micrograms/ mL compared to controls; this was abolished by the selective caspase-3 inhibitor Ac-Asp-Gln-Thr-Asp-H (50 microM), which also significantly reduced the cell death resulting from GSPE (500 micrograms/mL). The antioxidant N-acetylcysteine (NAC, 100 microM) reduced cell death induced by GSPE (500 micrograms/mL) but failed to attenuate caspase-3 activation. Collectively, the authors conclude that higher doses of GSPE could cause apoptotic cell injury via effector caspase-3 activation and subsequent induction of ROS generation. Consumers may take higher doses of dietary supplements in the belief that natural herbs have no major side effects. This study demonstrates that dosages of GSPE should be optimized to avoid potential harmful pro-oxidant effects.
authors.affiliation: Tang Center for Herbal Medicine Research, Emergency Resuscitation Research Center, and Department of Medicine, Pritzker School of Medicine, University of Chicago, Chicago, IL, USA.
authors.forename: Zuo-Hui
authors.initials: ZH
authors.lastname: Shao
authors.forename: Terry L
authors.initials: TL
authors.lastname: Vanden Hoek
authors.forename: Jingtian
authors.initials: J
authors.lastname: Xie
authors.forename: Kim
authors.initials: K
authors.lastname: Wojcik
authors.forename: Kim Chai
authors.initials: KC
authors.lastname: Chan
authors.forename: Chang-Qing
authors.initials: CQ
authors.lastname: Li
authors.forename: Kimm
authors.initials: K
authors.lastname: Hamann
authors.forename: Yimin
authors.initials: Y
authors.lastname: Qin
authors.forename: Paul T
authors.initials: PT
authors.lastname: Schumacker
authors.forename: Lance B
authors.initials: LB
authors.lastname: Becker
authors.forename: Chun-Su
authors.initials: CS
authors.lastname: Yuan
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000473:pathology; D048429:Cell Size / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002642:Chick Embryo; D004789:Enzyme Activation; D005452:Fluoresceins / Q000378:metabolism; D006352:Heart Ventricles / Q000166:cytology; D007770:L-Lactate Dehydrogenase / Q000096:biosynthesis; D008856:Microscopy, Fluorescence; D032383:Myocytes, Cardiac / Q000378:metabolism*; D016877:Oxidants / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D010936:Plant Extracts / Q000008:administration & dosage / Q000009:adverse effects; D044945:Proanthocyanidins / Q000008:administration & dosage / Q000009:adverse effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012639:Seeds; D027843:Vitis
chemical_list: D005452:Fluoresceins; D016877:Oxidants; D010936:Plant Extracts; D044945:Proanthocyanidins; D017382:Reactive Oxygen Species; C037631:2',7'-dichlorofluorescein; D007770:L-Lactate Dehydrogenase; D053148:Caspase 3; D020169:Caspases; D000111:Acetylcysteine