%0 Journal Article
%T Kinetic Characterization of Na,K-ATPase Inhibition by the Acetaminophen Metabolite N-Acetylbenzoquinoneimine
%A Jeff B. Helms
%A Lauren P. Saunders
%A Jamie Meyer
%A Charles J. Costa
%A Eric Plowman
%A Nick Williford
%A Matthew Corbitt
%A Jeremy P. Holden
%A Craig Gatto
%J Open Journal of Molecular and Integrative Physiology
%P 1-17
%@ 2162-2167
%D 2015
%I Scientific Research Publishing
%R 10.4236/ojmip.2015.51001
%X N-acetylbenzoquinoneimine (NABQI) is a toxic metabolite of the common analgesic acetaminophen (APAP). NABQI is an electrophilic intermediate formed via the oxidation of APAP within the cytochrome P450 system. Within the normally recommended low-dose use of APAP, NABQI is a minor metabolite which is either quickly reduced back to APAP or conjugated to Glutathione (GSH) producing an innocuous by-product. However, with overdose or prolonged high-dose usage of acetaminophen, GSH levels can become depleted and the bioactive NABQI is thought to form adducts with proteins and oxidize protein sulfhydryls producing intra- and intermolecular disulfide bridges in proteins. In this work we investigated the effect of NABQI on purified kidney Na,K-ATPase to see if the clinical renal insufficiencies seen in APAP overdose may be linked to inhibition of the Na,K-ATPase. Our work has shown that NABQI does indeed inhibit the Na,K-ATPase in a dose dependent (IC<sub>50</sub> = 19.8 ¡À 2.9 ¦ÌM) and irreversible manner. Interestingly, brief storage of NABQI at -20¡ãC eliminates the irreversible effects of the compound, and leads to a product that remains a potent reversible inhibitor of the Na,K-ATPase (IC<sub>50</sub> = 58.7 ¡À 19.5 ¦ÌM). Further, the reversible inhibition produced by stored NABQI competes with <i>para</i>-nitrop.
%K Na
%K K-ATPase
%K Paracetamol
%K N-Acetylbenzoquinoneimine
%K Overdose
%K Renal
%K Electrophillic
%U http://www.scirp.org/journal/PaperInformation.aspx?PaperID=53743