Abstract
It was previously shown that a necrogenic dose of acetaminophen (APAP) induced the 25- and 70-kDa heat shock proteins (hsp25 and hsp70i) in mouse liver, whereas nonnecrogenic doses failed to alter the level of either hsp. A strong correlation between the intralobular sites of APAP arylation of protein and hsp induction suggested that APAP-induced protein denaturation may play a role in triggering hsp induction. This study was conducted to determine whether APAP arylation of protein without concurrent toxicity could cause hsp induction. APAP (250 mg/kg i.p.) hepatotoxicity was eliminated using N-acetylcysteine (NAC, 300 mg/kg i.p.) or the cytochrome P-450 inhibitor diallyl sulfide (200 mg/kg p.o.). NAC did not inhibit APAP arylation of protein when administered 1 or 3 hr after the APAP dose but decreased binding by ∼50% when administered at the same time as the APAP dose. Even though APAP hepatotoxicity was blocked by NAC administered 0 or 1 hr after the APAP dose, NAC did not inhibit the induction of hsp25 or hsp70i, indicating that APAP arylation of protein may play a key role in triggering hsp induction. Diallyl sulfide blocked APAP arylation of protein, hepatotoxicity, and induction of both hsps. These data are consistent with the hypothesis that toxicant adduction of protein triggers hsp induction.
Footnotes
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Send reprint requests to: Dr. Stephen M. Roberts, Center for Environmental and Human Toxicology, University of Florida, Box 110885, Gainesville, FL 32611. E-mail: smr{at}ufl.edu
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↵1 This work was supported by National Institutes of Health Grant ES07213.
- Abbreviations:
- hsp
- heat shock protein
- SDS
- sodium dodecyl sulfate
- PAGE
- polyacrylamide gel electrophoresis ALT, alanine aminotransferase
- APAP
- acetaminophen
- AMAP
- 3′-hydroxyacetanilide
- DAS
- diallyl sulfide
- GSH
- glutathione
- NAC
- N-acetylcysteine
- Received July 21, 1997.
- Accepted March 2, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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