Protection against hepatotoxicity by a single dose of amphetamine: the potential role of heat shock protein induction.
Amphetamine has been shown previously to increase levels of the inducible 70-kDa heat shock protein (hsp70i) in mouse liver. In the present study, the hepatic concentrations of a variety of hsps in livers of mice pretreated with amphetamine (15 mg/kg, i.p.) were evaluated, and the time course of hsp induction was examined. Amphetamine treatment caused an acute rise in core body temperature to 40 degrees C for at least 1 hr and increased hsp25 and hsp70i levels, as measured by Western blotting, at 6, 24, 48, and 72 hr with no apparent induction of other hsps (hsp60, hsc70, or hsp90). A 72-hr amphetamine pretreatment lowered the hepatotoxicity of an acute dose of acetaminophen (350 mg/kg, i.p.) or bromobenzene (0.45 ml/kg, i.p.), but had no effect on the toxicity of carbon tetrachloride (0.04 ml/kg, i.p.) or cocaine (50 mg/kg, i.p.), as measured by serum alanine aminotransferase activity and histopathological analysis. No protection from acetaminophen or bromobenzene hepatotoxicity was observed when hepatotoxicant administration was delayed until hsp levels had returned to control values (144 hr after amphetamine pretreatment). Amphetamine pretreatment did not reduce in vivo covalent binding to proteins of radiolabeled [3H]acetaminophen, [14C]bromobenzene, [14C]carbon tetrachloride, or [3H]cocaine, indicating that the protective effects were not due to inhibition of reactive metabolite formation from these toxicants. These results suggest that elevated levels of hsp25 and hsp70i provide protection against acetaminophen and bromobenzene hepatotoxicity.
Salminen
W F
WF
Department of Pharmacology, J. Hillis Miller Health Science Center, University of Florida, Gainesville, USA.
Voellmy
R
R
Roberts
S M
SM
D000082:Acetaminophen / Q000633:toxicity; D000661:Amphetamine / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D001969:Bromobenzenes / Q000633:toxicity; D002251:Carbon Tetrachloride / Q000633:toxicity; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology / Q000517:prevention & control*; D003042:Cocaine / Q000633:toxicity; D005334:Fever / Q000139:chemically induced / Q000503:physiopathology; D006360:Heat-Shock Proteins / Q000096:biosynthesis*; D006979:Hyperthermia, Induced; D007150:Immunohistochemistry; D008099:Liver / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR
D001969:Bromobenzenes; D006360:Heat-Shock Proteins; D000082:Acetaminophen; D000661:Amphetamine; D002251:Carbon Tetrachloride; C032036:bromobenzene; D003042:Cocaine