Differential heat shock protein induction by acetaminophen and a nonhepatotoxic regioisomer, 3'-hydroxyacetanilide, in mouse liver.
The effect of acetaminophen (APAP) and 3'-hydroxyacetanilide (AMAP) on heat shock protein (hsp) induction in mouse liver was examined using Western blotting and immunohistochemistry. Western blots from APAP (200 mg/kg i.p.)-treated mice showed increased hsp25 levels at 6 and 24 hr and increased hsp70i levels at 3, 6 and 24 hr. No apparent induction was observed for other hsps (hsp60, hsc70, or hsp90). No increase in the levels of any of the hsps was apparent in Western blots from AMAP (1000 mg/kg i.p.)-treated mice. Immunohistochemical localization of hsp25 and hsp70i in the liver after APAP treatment showed increases in the levels of both hsps within the zone of affected cells at early time points (3 and 6 hr), but at 24 hr, elevated hsp25 levels were observed primarily in cells on the periphery of the lesions. Hepatocytes with increased hsp25 or hsp70i levels also had detectable reactive metabolite binding from APAP, as determined using immunostaining. No hepatotoxicity was observed in liver sections from AMAP treated mice, even though immunostaining indicated widespread reactive metabolite binding. Immunostaining for hsps confirmed that no increase in hsp25 or hsp70i levels occurred in response to this binding. Differences in hsp expression after APAP vs. AMAP may be due to differences in protein targets adducted by their respective reactive metabolites, in the concentrations of adducted proteins or perhaps in some other differential effect necessary for hsp upregulation.
Salminen
W F
WF
Department of Pharmacology and Therapeutics, J. Hillis Miller Health Science Center, University of Florida, Gainesville 32611, USA.
Voellmy
R
R
Roberts
S M
SM
D000082:Acetaminophen / Q000378:metabolism / Q000633:toxicity*; D018712:Analgesics, Non-Narcotic / Q000633:toxicity*; D000818:Animals; D006360:Heat-Shock Proteins / Q000096:biosynthesis*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D013237:Stereoisomerism
D018712:Analgesics, Non-Narcotic; D006360:Heat-Shock Proteins; D000082:Acetaminophen