Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.14 (ATP synthase)
 7,042 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Overdose of acetaminophen (APAP) causes severe centrilobular hepatic necrosis in humans and experimental animals. Here, to explore its mechanism, we administered APAP at subtoxic (150 mg/kg ip) and toxic (500 mg/kg ip) doses to overnight fasted mice. Animals were sacrificed at different time points from 15 min to 4 h postinjection. We assessed liver toxicity by plasma ALT activity and by electron microscopy. Using nylon filter arrays and RTQPCR, we performed genomics analysis in liver. We ran proteomics on liver mitochondrial subfractions using the newly developed quantitative fluorescent 2D-DIGE method (Amersham Pharmacia Biotech UK Limited). As soon as 15 min postinjection, centrilobular hepatocyte mitochondria were already slightly enlarged and GSH total content dropped by a third at top dose. GM-CSF mRNA, which is a granulocyte specific gene likely coming from resident Kupffer cells, was also induced to its maximum of 3-fold at both doses. Chaperone proteins Hsp10 and Hsp60 were readily decreased by half in mitochondria at both doses, most likely by leaking into cytoplasm. Although APAP is known as an apoptotic trigger, no apoptosis was observed at any time point. Most of the protein changes in mitochondria were present at 15 min postinjection, thus preceding most of the gene regulations. The decrease of ATP synthase subunits and beta-oxidation pathway proteins indicated a loss of energy production. As the morphology of mitochondria was also affected very early at top dose, we concluded that APAP toxicity was a direct action of its known reactive metabolite NAPQI, rather than a consequence of gene regulation. However, the latter will either worsen the toxicity or lead toward cell recovery depending on the cellular damage level.
 ...
PMID:Genomics and proteomics analysis of acetaminophen toxicity in mouse liver. 1175 93

Acetaminophen (APAP), a widely used analgesic/antipyretic agent, can cause liver injury through increased nitrative stress, leading to protein nitration. However, the identities of nitrated proteins and their roles in hepatotoxicity are poorly understood. Thus, we aimed at studying the mechanism of APAP-induced hepatotoxicity by systematic identification and characterization of nitrated proteins in the absence or presence of an antioxidant, N-acetylcysteine (NAC). The levels of nitrated proteins markedly increased at 2h in mice exposed to a single APAP dose (350mg/kg ip), which caused severe liver necrosis at 24h. Protein nitration and liver necrosis were minimal in mice exposed to nontoxic 3-hydroxyacetanilide or animals co-treated with APAP and NAC. Mass-spectral analysis of the affinity-purified nitrated proteins identified numerous mitochondrial and cytosolic proteins, including mitochondrial aldehyde dehydrogenase, Mn-superoxide dismutase, glutathione peroxidase, ATP synthase, and 3-ketoacyl-CoA thiolase, involved in antioxidant defense, energy supply, or fatty acid metabolism. Immunoprecipitation followed by immunoblot with anti-3-nitrotyrosine antibody confirmed that the aforementioned proteins were nitrated in APAP-exposed mice but not in NAC-cotreated mice. Consistently, NAC cotreatment significantly restored the suppressed activity of these enzymes. Thus, we demonstrate a new mechanism by which many nitrated proteins with concomitantly suppressed activity promotes APAP-induced mitochondrial dysfunction and hepatotoxicity.
 ...
PMID:Robust protein nitration contributes to acetaminophen-induced mitochondrial dysfunction and acute liver injury. 2345 65

The acute liver failure (ALF) induced by acetaminophen (APAP) is closely related to oxidative damage and depletion of hepatic glutathione, consequently changes in cell energy metabolism and mitochondrial dysfunction have been observed after APAP overdose. Diphenyl diselenide [(PhSe)2], a simple organoselenium compound with antioxidant properties, previously demonstrated to confer hepatoprotection. However, little is known about the protective mechanism on mitochondria. The main objective of this study was to investigate the effects (PhSe)2 to reduce mitochondrial dysfunction and, secondly, compare in the liver homogenate the hepatoprotective effects of the (PhSe)2 to the N-acetylcysteine (NAC) during APAP-induced ALF to validate our model. Mice were injected intraperitoneal with APAP (600 mg/kg), (PhSe)2 (15.6 mg/kg), NAC (1200 mg/kg), APAP+(PhSe)2 or APAP+NAC, where the (PhSe)2 or NAC treatment were given 1 h following APAP. The liver was collected 4 h after overdose. The plasma alanine and aspartate aminotransferase activities increased after APAP administration. APAP caused a remarkable increase of oxidative stress markers (lipid peroxidation, reactive species and protein carbonylation) and decrease of the antioxidant defense in the liver homogenate and mitochondria. APAP caused a marked loss in the mitochondrial membrane potential, the mitochondrial ATPase activity, and the rate of mitochondrial oxygen consumption and increased the mitochondrial swelling. All these effects were significantly prevented by (PhSe)2. The effectiveness of (PhSe)2 was similar at a lower dose than NAC. In summary, (PhSe)2 provided a significant improvement to the mitochondrial redox homeostasis and the mitochondrial bioenergetics dysfunction caused by membrane permeability transition in the hepatotoxicity APAP-induced.
...
PMID:New therapeutic approach: diphenyl diselenide reduces mitochondrial dysfunction in acetaminophen-induced acute liver failure. 2434 62