Department of Pediatrics, Little Rock, AR, United States.
Chem Biol Interact. 2011 Feb 1;189(3):222-9. doi: 10.1016/j.cbi.2010.12.001. Epub 2010 Dec 9.
Standard assays to assess acetaminophen (APAP) toxicity in animal models include determination of ALT (alanine aminotransferase) levels and examination of histopathology of liver sections. However, these assays do not reflect the functional capacity of the injured liver. To examine a functional marker of liver injury, the pharmacokinetics of indocyanine green (ICG) were examined in mice treated with APAP, saline, or APAP followed by N-acetylcysteine (NAC) treatment.Male B6C3F1 mice were administered APAP (200 mg/kg IP) or saline. Two additional groups of mice received APAP followed by NAC at 1 or 4 h after APAP. At 24 h, mice were injected with ICG (10 mg/kg IV) and serial blood samples (0, 2, 10, 30, 50 and 75 min) were obtained for determination of serum ICG concentrations and ALT. Mouse livers were removed for measurement of APAP protein adducts and examination of histopathology. Toxicity (ALT values and histology) was significantly increased above saline treated mice in the APAP and APAP/NAC 4 h mice. Mice treated with APAP/NAC 1 h had complete protection from toxicity. APAP protein adducts were increased in all APAP treated groups and were highest in the APAP/NAC 1 h group. Pharmacokinetic analysis of ICG demonstrated that the total body clearance (Cl(T)) of ICG was significantly decreased and the mean residence time (MRT) was significantly increased in the APAP mice compared to the saline mice. Mice treated with NAC at 1 h had Cl(T) and MRT values similar to those of saline treated mice. Conversely, mice that received NAC at 4 h had a similar ICG pharmacokinetic profile to that of the APAP only mice. Prompt treatment with NAC prevented loss of functional activity while late treatment with NAC offered no improvement in ICG clearance at 24 h. ICG clearance in mice with APAP toxicity can be utilized in future studies testing the effects of novel treatments for APAP toxicity.
标准的评估动物模型中对乙酰氨基酚（APAP）毒性的测定方法包括测定丙氨酸氨基转移酶（ALT）水平和检查肝切片的组织病理学。然而，这些测定方法并不能反映受损肝脏的功能能力。为了检查肝损伤的功能标志物，研究人员检查了用 APAP、生理盐水或 APAP 后用 N-乙酰半胱氨酸（NAC）治疗的小鼠中吲哚菁绿（ICG）的药代动力学。雄性 B6C3F1 小鼠给予 APAP（200 mg/kg IP）或生理盐水。另外两组小鼠在给予 APAP 后 1 或 4 小时给予 NAC。在 24 小时时，给小鼠注射 ICG（10 mg/kg IV），并采集连续血样（0、2、10、30、50 和 75 分钟）以测定血清 ICG 浓度和 ALT。取出小鼠肝脏进行 APAP 蛋白加合物的测量和组织病理学检查。APAP 和 APAP/NAC 4 小时组的 ALT 值和组织学毒性明显高于生理盐水处理的小鼠。APAP/NAC 1 小时组的小鼠完全免受毒性的影响。所有 APAP 处理组的 APAP 蛋白加合物均增加，APAP/NAC 1 小时组最高。ICG 的药代动力学分析表明，与生理盐水组相比，APAP 组的总清除率（Cl(T)）显著降低，平均驻留时间（MRT）显著增加。在 1 小时时给予 NAC 的小鼠的 Cl(T)和 MRT 值与生理盐水处理的小鼠相似。相反，在 4 小时时给予 NAC 的小鼠的 ICG 药代动力学特征与仅给予 APAP 的小鼠相似。及时给予 NAC 可防止功能活性丧失，而晚期给予 NAC 不能改善 24 小时时 ICG 的清除率。在有 APAP 毒性的小鼠中，ICG 的清除率可用于未来测试新型 APAP 毒性治疗方法效果的研究。
