Comparison of inhibitory effects between acetaminophen-glutathione conjugate and reduced glutathione in human glutathione reductase
Jazyk angličtina Země Velká Británie, Anglie Médium print-electronic
Typ dokumentu srovnávací studie, časopisecké články, práce podpořená grantem
PubMed
24038001
DOI
10.1002/jat.2914
Knihovny.cz E-zdroje
- Klíčová slova
- acetaminophen toxicity, glutathione, glutathione reductase,
- MeSH
- erytrocyty enzymologie MeSH
- glutathion toxicita MeSH
- glutathiondisulfid metabolismus MeSH
- glutathionreduktasa antagonisté a inhibitory metabolismus MeSH
- lidé MeSH
- paracetamol analogy a deriváty toxicita MeSH
- rekombinantní proteiny metabolismus MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- srovnávací studie MeSH
- Názvy látek
- 3-(glutathion-S-yl)acetaminophen MeSH Prohlížeč
- glutathion MeSH
- glutathiondisulfid MeSH
- glutathionreduktasa MeSH
- paracetamol MeSH
- rekombinantní proteiny MeSH
Acetaminophen overdose is the most frequent cause of acute liver injury. The main mechanism of acetaminophen toxicity has been attributed to oxidation of acetaminophen. The oxidation product is very reactive and reacts with glutathione generating acetaminophen-glutathione conjugate (APAP-SG). Although this conjugate has been recognized to be generally nontoxic, we have found recently that APAP-SG could produce a toxic effect. Therefore, the aim of our study was to estimate the toxicity of purified APAP-SG by characterizing the inhibitory effect in human glutathione reductase (GR) and comparing that to the inhibitory effect of the natural inhibitor reduced glutathione. We used two types of human GR: recombinant and freshly purified from red blood cells. Our results show that GR was significantly inhibited in the presence of both APAP-SG and reduced glutathione. For example, the enzyme activity of recombinant and purified GR was reduced in the presence of 4 mm APAP-SG (with 0.5 mm glutathione disulfide) by 28% and 22%, respectively. The type of enzyme inhibition was observed to be competitive in the cases of both APAP-SG and glutathione. As glutathione inhibits GR activity in cells under physiological conditions, the rate of enzyme inhibition ought to be weaker in the case of glutathione depletion that is typical of acetaminophen overdose. Notably, however, enzyme activity likely remains inhibited due to the presence of APAP-SG, which might enhance the pro-oxidative status in the cell. We conclude that our finding could reflect some other pathological mechanism that may contribute to the toxicity of acetaminophen.
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