Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
2581000 | Chemico-Biological Interactions | 2011 | 8 Pages |
Abstract
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 (200Â mg/kg IP) or saline. Two additional groups of mice received APAP followed by NAC at 1 or 4Â h after APAP. At 24Â h, mice were injected with ICG (10Â mg/kg IV) and serial blood samples (0, 2, 10, 30, 50 and 75Â 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 4Â h mice. Mice treated with APAP/NAC 1Â h had complete protection from toxicity. APAP protein adducts were increased in all APAP treated groups and were highest in the APAP/NAC 1Â h group. Pharmacokinetic analysis of ICG demonstrated that the total body clearance (ClT) 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 1Â h had ClT and MRT values similar to those of saline treated mice. Conversely, mice that received NAC at 4Â 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 24Â h. ICG clearance in mice with APAP toxicity can be utilized in future studies testing the effects of novel treatments for APAP toxicity.
Keywords
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Authors
Alessandra Milesi-Hallé, Susan M. Abdel-Rahman, Aliza Brown, Sandra S. McCullough, Lynda Letzig, Jack A. Hinson, Laura P. James,