Salminen W F, Voellmy R, Roberts S M
Department of Pharmacology, J. Hillis Miller Health Science Center, University of Florida, Gainesville, USA.
Toxicol Appl Pharmacol. 1997 Dec;147(2):247-58. doi: 10.1006/taap.1997.8290.
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.
先前的研究表明，苯丙胺可提高小鼠肝脏中诱导型70 kDa热休克蛋白（hsp70i）的水平。在本研究中，评估了用苯丙胺（15 mg/kg，腹腔注射）预处理的小鼠肝脏中多种热休克蛋白的肝浓度，并检测了热休克蛋白诱导的时间进程。苯丙胺处理使核心体温急性升高至40℃至少1小时，并通过蛋白质免疫印迹法检测发现，在6、24、48和72小时时hsp25和hsp70i水平升高，而其他热休克蛋白（hsp60、hsc70或hsp90）无明显诱导。苯丙胺预处理72小时可降低急性剂量对乙酰氨基酚（350 mg/kg，腹腔注射）或溴苯（0.45 ml/kg，腹腔注射）的肝毒性，但对四氯化碳（0.04 ml/kg，腹腔注射）或可卡因（50 mg/kg，腹腔注射）的毒性无影响，这通过血清丙氨酸氨基转移酶活性和组织病理学分析来衡量。当肝毒性物质给药延迟至热休克蛋白水平恢复到对照值（苯丙胺预处理后144小时）时，未观察到对乙酰氨基酚或溴苯肝毒性的保护作用。苯丙胺预处理并未降低体内放射性标记的[3H]对乙酰氨基酚、[14C]溴苯、[14C]四氯化碳或[3H]可卡因与蛋白质的共价结合，表明保护作用并非由于抑制这些毒物的反应性代谢产物形成。这些结果表明，hsp25和hsp70i水平升高可提供针对对乙酰氨基酚和溴苯肝毒性的保护作用。
