Subcellular binding and effects on calcium homeostasis produced by acetaminophen and a nonhepatotoxic regioisomer, 3'-hydroxyacetanilide, in mouse liver.
Acetaminophen (250 mg/kg) administered intraperitoneally to fasted, phenobarbital-induced mice produced hepatotoxicity. No hepatotoxicity was observed after the administration of the regioisomer 3'-hydroxyacetanilide (600 mg/kg). Similar levels of covalent binding to liver homogenates occurred in mice receiving either acetaminophen or 3'-hydroxyacetanilide at these doses. However, subcellular fractionation techniques revealed that the acetaminophen treatment produced greater levels of covalent binding to mitochondrial proteins than 3'-hydroxyacetanilide. In addition, acetaminophen depleted mitochondrial glutathione levels more extensively than 3'-hydroxyacetanilide. Plasma membrane calcium-ATPase activity was reduced to 79.8% and 55.7% of control values at 1 h and 6 h, respectively, following the administration of acetaminophen. No inhibition of this enzyme was detected in mice receiving 3'-hydroxyacetanilide. Acetaminophen also induced alterations in mitochondrial calcium levels and decreased the ability of isolated mitochondria to sequester calcium. These effects were not produced by 3'-hydroxyacetanilide. Our results indicate that acetaminophen induces alterations in calcium homeostasis while 3'-hydroxyacetanilide does not.
Tirmenstein
M A
MA
Department of Medicinal Chemistry, University of Washington, Seattle 98195.
Nelson
S D
SD
D000082:Acetaminophen / Q000494:pharmacology*; D000083:Acetanilides / Q000494:pharmacology*; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D002462:Cell Membrane / Q000201:enzymology; D005978:Glutathione / Q000031:analogs & derivatives / Q000378:metabolism; D019803:Glutathione Disulfide; D006706:Homeostasis / Q000187:drug effects; D007536:Isomerism; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism*; D012016:Reference Values; D013347:Subcellular Fractions / Q000378:metabolism
D000083:Acetanilides; D000700:Analgesics; D000082:Acetaminophen; C026137:3-hydroxyacetanilide; D000252:Calcium-Transporting ATPases; D005978:Glutathione; D002118:Calcium; D019803:Glutathione Disulfide