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 induci ble 70-kDa heat shock protein (hsp70i) in mouse liver. In the present study, the hepatic concentrations of a variety of hsps in livers of mi ce pretreated with amphetamine (15 mg/kg, ip) were evaluated, and the time course of hsp induction was examined. Amphetamine treatment cause d 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 blo tting, at 6, 24, 48, and 72 hr with no apparent induction of other hsp s (hsp60, hsc70, or hsp90). A 72-hr amphetamine pretreatment lowered t he hepatotoxicity of an acute dose of acetaminophen (350 mg/kg, ip) or bromobenzene (0.45 ml/kg, ip), but had no effect on the toxicity of c arbon tetrachloride (0.04 ml/kg, ip) or cocaine (50 mg/kg, ip), as mea sured by serum alanine aminotransferase activity and histopathological analysis. No protection from acetaminophen or bromobenzene hepatotoxi city was observed when hepatotoxicant administration was delayed until hsp levels had returned to control values (144 hr after amphetamine p retreatment). Amphetamine pretreatment did not reduce in vivo covalent binding to proteins of radiolabeled [H-3]acetaminophen, [C-14]bromobe nzene, [C-14]carbon tetrachloride, or [H-3]cocaine, indicating that th e protective effects were not due to inhibition of reactive metabolite formation from these toxicants. These results suggest that elevated l evels of hsp25 and hsp70i provide protection against acetaminophen and bromobenzene hepatotoxicity. (C) 1997 Academic Press.