Involvement of Oxidative Stress and Poly (ADP-ribose) Polymerase Activation in 3-Nitropropionic Acid-induced Cytotoxicity in Human Neuroblastoma Cells.
- Author:
Eunjoo NAM
1
;
Young Jae LEE
;
Young Ah OH
;
Jin Ah JUNG
;
Hye In IM
;
Seong Eun KOH
;
Sungho MAENG
;
Wan Seok JOO
;
Yong Sik KIM
Author Information
1. Department of Pharmacology, Seoul National University College of Medicine and Neuroscience Research Institute, Medical Research Center, Seoul 110-799, Korea. kimysu@plaza.snu.ac.kr
- Publication Type:Original Article
- Keywords:
3-Nitropropionic acid;
Cytotoxicity;
Oxidative stress;
DNA damage;
Poly (ADP-ribose) polymerase;
3-Aminobenzamide
- MeSH:
Acetylcysteine;
Cell Death;
Cell Survival;
DNA;
DNA Damage;
Electron Transport;
Glutathione;
Humans*;
Mitochondria;
Neuroblastoma*;
Oxidative Stress*;
Reactive Oxygen Species
- From:The Korean Journal of Physiology and Pharmacology
2003;7(6):325-331
- CountryRepublic of Korea
- Language:English
-
Abstract:
3-Nitropropionic acid (3-NP) inhibits electron transport in mitochondria, leading to a metabolic failure. In order to elucidate the mechanism underlying this toxicity, we examined a few biochemical changes possibly involved in the process, such as metabolic inhibition, generation of reactive oxygen species (ROS), DNA strand breakage, and activation of Poly (ADP-ribose) polymerase (PARP). Exposure of SK-N-BE (2) C neuroblastoma cells to 3-NP for 48 h caused actual cell death, while inhibition of mitochondrial function was readily observed when exposed for 24 h to low concentrations (0.2~2 mM) of 3-NP. The earliest biochemical change detected with low concentration of 3-NP was an accumulation of ROS (4 h after 3-NP exposure) followed by degradation of DNA. PARP activation by damaged DNA was also detectable, but at a later time. The accumulation of ROS and DNA strand breakage were suppressed by the addition of glutathione or N-acetyl-L-cysteine (NAC), which also partially restored mitochondrial function and cell viability. In addition, inhibition of PARP also reduced the 3-NP-induced DNA strand breakage and cytotoxicity. These results suggest that oxidative stress and activation of PARP are the major factors in 3-NP-induced cytotoxicity, and that the inhibition of these factors may be useful in protecting neuroblastoma cells from 3-NP-induced toxicity.
