Administration of the non-metabolizable organic
anion indocyanine green (ICG) prior to a toxic dose of
acetaminophen (4-
acetamidophenol;
APAP) reduces liver injury 24h after dosing. ICG also produces a dose-dependent decrease in bile flow in mice and rats. Studies in bile duct-cannulated rats suggest that
cholestasis can play a role in this protection. This study was conducted to determine if the ability of model organic
anions to produce
cholestasis is relevant to the protection against
APAP hepatotoxicity afforded by ICG. In these studies, overnight fasted male CD-1 mice were dosed (i.v.) with the cholestatic
dyes bromcresol green (BCG, 30 micromol/kg) and
rose bengal (RB, 60 micromol/kg) immediately prior
APAP administration (500 mg/kg, i.p.). Other groups of mice received the non-cholestatic
dyes dibromosulphthalein (DBSP, 150 micromol/kg) and amaranth (AM, 300 micromol/kg) prior to
APAP. Controls were given vehicle only. Hepatocellular
necrosis was evident at 24 h in control mice receiving
APAP. Pretreatment with the cholestatic
dyes BCG and RB decreased the severity of hepatocellular
necrosis induced by
APAP. However, administration of the non-cholestatic
dyes DBSP and AM did not alter
APAP-induced liver damage.
Glutathione replenishment was not altered by pretreatment with any of these
dyes. Furthermore, ICG protected mice against
carbon tetrachloride (CCl4) hepatotoxicity. Since CCl4 undergoes minimal biliary excretion and does not compete for biliary transport function, this finding supports the notion that
cholestasis itself rather than competition for canalicular transporters is central to the hepatoprotection by ICG and other cholephilic
dyes.