Changes in susceptibility to acetaminophen-induced liver injury by the organic anion indocyanine green.
The non-metabolizable organic anion indocyanine green (ICG) has been shown previously to reduce markedly the biliary secretion of acetaminophen, particularly the glutathione conjugate of APAP (APAP-GSH), suggesting that this APAP metabolite may compete with other xenobiotics for excretion into the bile via a canalicular organic anion transport process. This study was conducted to determine whether changes in the biliary disposition of APAP induced by ICG could lead to alterations in susceptibility to APAP hepatotoxicity. To investigate this, groups of overnight-fasted male CD-1 mice received 30 micromol ICG/kg, intravenously, immediately prior to APAP dosing (500 mg/kg, ip). Controls were given propylene glycol vehicle. Mice were killed at 4 h after APAP challenge for immunochemical analysis of cytosolic protein arylation and determination of non-protein sulfhydryl (NPSH) depletion, or at 12 and 24 h for biochemical and histological assessment of liver injury. Elevated plasma sorbitol dehydrogenase activity and centrilobular hepatocellular necrosis was present in control mice receiving APAP at 12 and 24 h. Treatment with ICG did not alter susceptibility to APAP toxicity when measured at 12 h after challenge. However, the severity of histologic lesions in the ICG-APAP group was significantly lower at 24 h after challenge. Furthermore, treatment with ICG did not alter APAP-induced glutathione depletion or cytosolic protein arylation. These data suggest that the organic anion ICG has a protective effect on APAP toxicity that promotes a faster recovery from liver injury.
Toxicology Program, Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269-2092, USA.
V M
VM
Silva
C
C
Chen
G E
GE
Hennig
H E
HE
Whiteley
J E
JE
Manautou
D000082:Acetaminophen / Q000633:toxicity*; D018712:Analgesics, Non-Narcotic / Q000633:toxicity*; D000818:Animals; D001646:Bile / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology* / Q000517:prevention & control*; D004396:Coloring Agents / Q000627:therapeutic use*; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D007150:Immunohistochemistry; D007208:Indocyanine Green / Q000627:therapeutic use*; D007064:L-Iditol 2-Dehydrogenase / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D013438:Sulfhydryl Compounds / Q000378:metabolism; D013997:Time Factors
D018712:Analgesics, Non-Narcotic; D004396:Coloring Agents; D013438:Sulfhydryl Compounds; D000082:Acetaminophen; D007064:L-Iditol 2-Dehydrogenase; D007208:Indocyanine Green