Roberts S M, Harbison R D, James R C
Center for Environmental and Human Toxicology, University of Florida, Gainesville, USA.
Toxicology. 1995 Mar 31;97(1-3):49-57. doi: 10.1016/0300-483x(94)02924-j.
Recent studies have shown that methamphetamine is capable of potentiating the hepatotoxicity of carbon tetrachloride in mice. In the present study, it was found that this potentiation is sensitive to changes in the timing of the methamphetamine dose relative to the administration of carbon tetrachloride. Potentiation of hepatotoxicity, measured using serum alanine aminotransferase (ALT) activity, was observed only if the dose of methamphetamine (15 mg/kg, i.p.) was given with, or 3 h after, the carbon tetrachloride dose (0.005 ml/kg, i.p.). No increase in carbon tetrachloride hepatotoxicity was evident when methamphetamine was administered 3 h before the carbon tetrachloride dose, or when given 6 or more hours after carbon tetrachloride. Increased covalent binding of carbon tetrachloride to proteins and lipids, shown previously to occur when methamphetamine and carbon tetrachloride are administered together, was not observed when methamphetamine was administered 3 h after the carbon tetrachloride dose and could not, therefore, account for the increased toxicity resulting from this treatment regimen. Pretreatment with the Kupffer cell inhibitor gadolinium chloride (10 mg/kg, i.v.) significantly diminished the potentiation of carbon tetrachloride hepatotoxicity by methamphetamine, suggesting that potentiation by methamphetamine involves, at least in part, a stimulation of Kupffer cells. Mice administered a methamphetamine pretreatment regimen known to induce behavioral sensitization displayed an enhanced potentiation of carbon tetrachloride hepatotoxicity, i.e. the extent of potentiation by methamphetamine was increased and the methamphetamine dose required for potentiation was diminished. Mice pretreated with a methamphetamine sensitization regimen were also found to be more responsive to the effects of morphine to enhance carbon tetrachloride hepatotoxicity. These observations suggest that there are important CNS, as well as hepatic, components in the potentiation of carbon tetrachloride-induced liver injury by methamphetamine and perhaps other drugs.
最近的研究表明，甲基苯丙胺能够增强四氯化碳对小鼠的肝毒性。在本研究中，发现这种增强作用对甲基苯丙胺给药时间相对于四氯化碳给药时间的变化敏感。仅当甲基苯丙胺剂量（15mg/kg，腹腔注射）与四氯化碳剂量（0.005ml/kg，腹腔注射）同时给予或在四氯化碳剂量后3小时给予时，才观察到使用血清丙氨酸转氨酶（ALT）活性测量的肝毒性增强。当甲基苯丙胺在四氯化碳剂量前3小时给药，或在四氯化碳给药后6小时或更长时间给药时，四氯化碳肝毒性没有明显增加。先前已表明，当甲基苯丙胺和四氯化碳一起给药时会发生四氯化碳与蛋白质和脂质的共价结合增加，但当甲基苯丙胺在四氯化碳剂量后3小时给药时未观察到这种情况，因此，这不能解释这种治疗方案导致的毒性增加。用库普弗细胞抑制剂氯化钆（10mg/kg，静脉注射）预处理可显著降低甲基苯丙胺对四氯化碳肝毒性的增强作用，这表明甲基苯丙胺的增强作用至少部分涉及对库普弗细胞的刺激。给予已知可诱导行为敏化的甲基苯丙胺预处理方案的小鼠，四氯化碳肝毒性的增强作用增强，即甲基苯丙胺的增强程度增加，增强所需的甲基苯丙胺剂量减少。还发现，用甲基苯丙胺敏化方案预处理的小鼠对吗啡增强四氯化碳肝毒性的作用更敏感。这些观察结果表明，在甲基苯丙胺以及可能其他药物增强四氯化碳诱导的肝损伤过程中，存在重要的中枢神经系统和肝脏成分。
