A metabolite of acetaminophen covalently binds to the 56 kDa selenium binding protein.
Acetaminophen is metabolized by cytochrome P450 to a reactive metabolite that covalently binds to proteins and this binding correlates with the hepatotoxicity. The major protein adduct was previously reported to be a 55 kDa protein that was detected on Western blots using antisera specific for 3-(cystein-S-yl)acetaminophen. In this study, the 55 kDa protein was isolated using a combination of ion exchange fast flow chromatography, hydroxyapatite HPLC and anion exchange HPLC. Amino acid sequences of 8 internal peptides from a trypsin digestion of the 55 kDa protein were found to have 97% homology with the deduced amino acid sequence from a cDNA that corresponds to a 56 kDa selenium binding protein. This is the first report of a specific protein to which a metabolite of acetaminophen covalently binds.
Pumford
N R
NR
Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock 72206.
Martin
B M
BM
Hinson
J A
JA
D000082:Acetaminophen / Q000031:analogs & derivatives* / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D001711:Biotransformation; D002352:Carrier Proteins / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D002458:Cell Fractionation; D002851:Chromatography, High Pressure Liquid; D002852:Chromatography, Ion Exchange; D003600:Cytosol / Q000378:metabolism; D007106:Immune Sera; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D008970:Molecular Weight; D010446:Peptide Fragments / Q000302:isolation & purification; D012643:Selenium / Q000302:isolation & purification / Q000378:metabolism*; D051137:Selenium-Binding Proteins; D012689:Sequence Homology, Nucleic Acid; D014462:Ultrafiltration
D002352:Carrier Proteins; D007106:Immune Sera; D010446:Peptide Fragments; C495176:Selenbp1 protein, mouse; C495177:Selenbp2 protein, mouse; D051137:Selenium-Binding Proteins; D000082:Acetaminophen; C063450:3-(cystein-S-yl)paracetamol; D012643:Selenium