Hepatotoxicity after 3'-hydroxyacetanilide administration to buthionine sulfoximine pretreated mice.
The administration of 3'-hydroxyacetanilide, a regioisomer of acetaminophen, to mice failed to produce hepatotoxicity even after the administration of diethyl maleate. In contrast, hepatotoxicity did occur when 3'-hydroxyacetanilide was administered to buthionine sulfoximine pretreated mice. Although the administration of 3'-hydroxyacetanilide in conjunction with either diethyl maleate or buthionine sulfoximine depleted total hepatic glutathione, only the combined buthionine sulfoximine-3'-hydroxyacetanilide treatment decreased hepatic mitochondrial glutathione concentrations to below 20% of control values. In addition, pretreatment with buthionine sulfoximine increased the amount of 3'-hydroxyacetanilide bound to mitochondrial proteins. These results, in conjunction without previous results on the involvement of mitochondrial damage in the pathogenesis of hepatotoxicity caused by acetaminophen, suggest a probable relationship between mitochondrial damage caused by the buthionine sulfoximine-3'-hydroxyacetanilide treatment and hepatotoxicity caused by this treatment.
Tirmenstein
M A
MA
Department of Medicinal Chemistry, University of Washington, Seattle 98195.
Nelson
S D
SD
D000082:Acetaminophen / Q000009:adverse effects* / Q000378:metabolism; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D019328:Buthionine Sulfoximine; D004347:Drug Interactions; D005978:Glutathione / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008298:Maleates / Q000494:pharmacology; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051379:Mice; D008930:Mitochondria, Liver / Q000378:metabolism; D013997:Time Factors
D000964:Antimetabolites, Antineoplastic; D008298:Maleates; D008717:Methionine Sulfoximine; D000082:Acetaminophen; D019328:Buthionine Sulfoximine; D000410:Alanine Transaminase; C014476:diethyl maleate; D005978:Glutathione