| RRC ID |
37692
|
| 著者 |
Shimada H, Hirai K, Simamura E, Hatta T, Iwakiri H, Mizuki K, Hatta T, Sawasaki T, Matsunaga S, Endo Y, Shimizu S.
|
| タイトル |
Paraquat toxicity induced by voltage-dependent anion channel 1 acts as an NADH-dependent oxidoreductase.
|
| ジャーナル |
J Biol Chem
|
| Abstract |
Paraquat (PQ), a herbicide used worldwide, causes fatal injury to organs upon high dose ingestion. Treatments for PQ poisoning are unreliable, and numerous deaths have been attributed inappropriate usage of the agent. It is generally speculated that a microsomal drug-metabolizing enzyme system is responsible for PQ toxicity. However, recent studies have demonstrated cytotoxicity via mitochondria, and therefore, the cytotoxic mechanism remains controversial. Here, we demonstrated that mitochondrial NADH-dependent PQ reductase containing a voltage-dependent anion channel 1 (VDAC1) is responsible for PQ cytotoxicity. When mitochondria were incubated with NADH and PQ, superoxide anion (O(2)(*)) was produced, and the mitochondria ruptured. Outer membrane extract oxidized NADH in a PQ dose-dependent manner, and oxidation was suppressed by VDAC inhibitors. Zymographic analysis revealed the presence of VDAC1 protein in the oxidoreductase, and the direct binding of PQ to VDAC1 was demonstrated using biotinylated PQ. VDAC1-overexpressing cells showed increased O(2)(*) production and cytotoxicity, both of which were suppressed in VDAC1 knockdown cells. These results indicated that a VDAC1-containing mitochondrial system is involved in PQ poisoning. These insights into the mechanism of PQ poisoning not only demonstrated novel physiological functions of VDAC protein, but they may facilitate the development of new therapeutic approaches.
|
| 巻・号 |
284(42)
|
| ページ |
28642-9
|
| 公開日 |
2009-10-16
|
| DOI |
10.1074/jbc.M109.033431
|
| PII |
S0021-9258(20)38230-2
|
| PMID |
19717555
|
| PMC |
PMC2781408
|
| MeSH |
Animals
Cell-Free System
HeLa Cells
Herbicides / toxicity*
Humans
Hydrogen Peroxide / pharmacology
Male
Microscopy, Electron / methods
Mitochondria / metabolism
NAD / metabolism*
NADH, NADPH Oxidoreductases / metabolism
NADH, NADPH Oxidoreductases / physiology*
Paraquat / toxicity*
Rats
Rats, Wistar
Reactive Oxygen Species
Voltage-Dependent Anion Channel 1 / metabolism
Voltage-Dependent Anion Channel 1 / physiology*
|
| IF |
4.238
|
| 引用数 |
20
|
|
WOS 分野
|
BIOCHEMISTRY & MOLECULAR BIOLOGY
|
| リソース情報 |
| ヒト・動物細胞 |
|
