James R C, Harbison R D, Roberts S M
Center for Environmental and Human Toxicology, University of Florida, Gainesville 32615.
Toxicol Appl Pharmacol. 1993 Feb;118(2):159-68. doi: 10.1006/taap.1993.1021.
Pretreatment of male ICR mice with the adrenergic agonist phenylpropanolamine (200 mg/kg, ip) resulted in a marked potentiation of hepatotoxicity produced by acetaminophen (400 mg/kg, ip). Enhanced liver necrosis with phenylpropanolamine pretreatment was evident both by measurement of serum aminotransferase activity and by histopathologic examination. Several lines of experimental evidence suggest this interaction is a result of the hepatic glutathione depression produced by alpha-adrenergic compounds, which adds to the glutathione depression caused by toxic, or nearly toxic, doses of acetaminophen. First, the potentiation of acetaminophen hepatotoxicity was time-dependent, being observed only when phenylpropanolamine was administered as a 3-hr pretreatment and not when given 1 hr before, with, or 3 hr after acetaminophen. The 3-hr interval between phenylpropanolamine and acetaminophen doses corresponds to the characteristic lag period required for alpha-adrenergic agents (including phenylpropanolamine) to produce significant and maximal effects on hepatic glutathione content. Second, dose-response relationships for phenylpropanolamine and acetaminophen were such that increased toxicity was observed only when the interaction was sufficient to lower hepatic glutathione concentrations below a level regarded as critical in preventing acetaminophen-induced hepatotoxicity. Third, when animals were pretreated with two nonadrenergic depletors of hepatic glutathione, diethylmaleate (125 mg/kg, ip) or the glutathione synthesis inhibitor buthionine sulfoximine (222 mg/kg, ip), at doses producing glutathione depletion approximating that observed with the adrenergic agents, acetaminophen hepatotoxicity was potentiated to the same extent. From these observations it is postulated that a variety of adrenergic compounds known to deplete hepatic glutathione by a moderate 30-50% may potentiate the hepatotoxicity of acetaminophen and possibly other hepatotoxic compounds for which glutathione conjugation is an important detoxification pathway.
用肾上腺素能激动剂去甲麻黄碱（200毫克/千克，腹腔注射）对雄性ICR小鼠进行预处理，可导致对乙酰氨基酚（400毫克/千克，腹腔注射）产生的肝毒性有明显增强作用。通过测量血清转氨酶活性和组织病理学检查均显示，去甲麻黄碱预处理可增强肝坏死。多条实验证据表明，这种相互作用是α-肾上腺素能化合物导致肝脏谷胱甘肽减少的结果，这进一步加重了由毒性或接近毒性剂量的对乙酰氨基酚所引起的谷胱甘肽减少。首先，对乙酰氨基酚肝毒性的增强具有时间依赖性，仅当去甲麻黄碱作为3小时预处理给药时才会观察到，而在对乙酰氨基酚给药前1小时、同时或给药后3小时给药则未观察到。去甲麻黄碱和对乙酰氨基酚给药间隔3小时对应于α-肾上腺素能药物（包括去甲麻黄碱）对肝脏谷胱甘肽含量产生显著和最大影响所需的特征性延迟期。其次，去甲麻黄碱和对乙酰氨基酚的剂量反应关系表明，只有当相互作用足以将肝脏谷胱甘肽浓度降低到被认为对预防对乙酰氨基酚诱导的肝毒性至关重要的水平以下时，才会观察到毒性增加。第三，当用两种非肾上腺素能的肝脏谷胱甘肽耗竭剂马来酸二乙酯（125毫克/千克，腹腔注射）或谷胱甘肽合成抑制剂丁硫氨酸亚砜胺（222毫克/千克，腹腔注射）对动物进行预处理时，在产生的谷胱甘肽耗竭程度与肾上腺素能药物观察到的程度相近的剂量下，对乙酰氨基酚的肝毒性增强程度相同。从这些观察结果推测，已知通过适度30 - 50%降低肝脏谷胱甘肽的多种肾上腺素能化合物可能会增强对乙酰氨基酚以及可能其他以谷胱甘肽结合作为重要解毒途径的肝毒性化合物的肝毒性。
