Roberts S M, Harbison R D, James R C
Center for Environmental and Human Toxicology, University of Florida, Gainesville.
J Pharmacol Exp Ther. 1994 Nov;271(2):1051-7.
Previous studies have indicated that adrenergic agents may potentiate the hepatotoxicity of compounds such as CCl4. Methamphetamine is a powerful central nervous system stimulating drug which also possesses significant adrenergic activity, and its effects on CCl4 hepatotoxicity were examined in male ICR mice. Cotreatment of mice with methamphetamine (15 mg/kg i.p.) resulted in a significant increase in the hepatocellular necrosis produced by minimally toxic to moderately toxic doses of CCl4 (0.005-0.02 ml/kg i.p.), as indicated by changes in serum alanine aminotransferase activity and by histopathologic examination. Methamphetamine alone at this dosage was not hepatotoxic. The ability of methamphetamine to potentiate CCl4 hepatotoxicity was dose-related and became statistically significant at methamphetamine doses of 10 mg/kg or greater. Pretreatment of animals with either the selective alpha-1 adrenoreceptor antagonist prazosin (5 mg/kg i.p.) or the selective alpha-2 adrenoreceptor antagonist yohimbine (5 mg/kg i.p.) blocked the methamphetamine potentiation. The increase in CCl4 toxicity produced by methamphetamine was not associated with an increase in hepatic concentrations of either CCl4 or one of its major metabolites, chloroform. The increase in toxicity was associated, however, with increases in the in vivo covalent binding of radiolabeled CCl4 to both hepatic proteins and lipids. The cause of the increased covalent binding was not identified, but did not appear to be related to methamphetamine-induced hepatic glutathione suppression. The results of this study suggest that methamphetamine potentiates CCl4 through an adrenoreceptor-related mechanism that may involve either the increased production or diminished conjugation of the reactive metabolites normally formed during the metabolism of CCl4.
先前的研究表明，肾上腺素能药物可能会增强诸如四氯化碳等化合物的肝毒性。甲基苯丙胺是一种强大的中枢神经系统刺激药物，也具有显著的肾上腺素能活性，本研究在雄性ICR小鼠中检测了其对四氯化碳肝毒性的影响。用甲基苯丙胺（15毫克/千克腹腔注射）与小鼠共同处理，导致由最低毒性至中等毒性剂量的四氯化碳（0.005 - 0.02毫升/千克腹腔注射）所产生的肝细胞坏死显著增加，这通过血清丙氨酸转氨酶活性的变化以及组织病理学检查得以证实。此剂量的甲基苯丙胺单独使用时并无肝毒性。甲基苯丙胺增强四氯化碳肝毒性的能力与剂量相关，且在甲基苯丙胺剂量为10毫克/千克或更高时具有统计学意义。用选择性α - 1肾上腺素能受体拮抗剂哌唑嗪（5毫克/千克腹腔注射）或选择性α - 2肾上腺素能受体拮抗剂育亨宾（5毫克/千克腹腔注射）对动物进行预处理，可阻断甲基苯丙胺的增强作用。甲基苯丙胺所导致的四氯化碳毒性增加与肝内四氯化碳或其主要代谢产物之一氯仿的浓度升高无关。然而，毒性增加与放射性标记的四氯化碳在体内与肝蛋白和脂质的共价结合增加有关。共价结合增加的原因尚未明确，但似乎与甲基苯丙胺诱导的肝谷胱甘肽抑制无关。本研究结果表明，甲基苯丙胺通过一种与肾上腺素能受体相关的机制增强四氯化碳的毒性，该机制可能涉及四氯化碳代谢过程中正常形成的反应性代谢产物的生成增加或结合减少。
