Altered disposition of acetaminophen in mice with a disruption of the Mrp3 gene.
MRP3 is an ABC transporter localized in the basolateral membrane of epithelial cells such as hepatocytes and enterocytes. In this study, the role of Mrp3 in drug disposition was investigated. Because Mrp3 preferentially transports glucuronide conjugates, we investigated the in vivo disposition of acetaminophen (APAP) and its metabolites. Mrp3+/+ and Mrp3-/- knockout mice received APAP (150 mg/kg), and bile was collected. Basolateral and canalicular excretion of APAP was also assessed in the isolated perfused liver. In separate studies, mice received 400 mg APAP/kg for assessment of hepatotoxicity. No differences were found in the biliary excretion of APAP, APAP-sulfate, and APAP-glutathione between Mrp3+/+ and Mrp3-/- mice. However, 20-fold higher accumulation of APAP-glucuronide (APAP-GLUC) was found in the liver of Mrp3-/- mice. Concomitantly, plasma APAP-GLUC content in Mrp3-/- mice was less than 10% of that in Mrp3+/+ mice. In addition, APAP-GLUC excretion in bile of Mrp3-/- mice was tenfold higher than in Mrp3+/+ mice. In the isolated perfused liver, we also found a strong decrease of APAP-GLUC secretion into the perfusate of Mrp3-/- livers. Plasma alanine aminotransferase (ALT), aspartate aminotransferase (AST), and histopathology showed that Mrp3-/- mice are more resistant to APAP hepatotoxicity than Mrp3+/+ mice, which is most likely a result of the faster repletion of hepatic GSH. In conclusion, basolateral excretion of APAP-GLUC in mice is nearly completely dependent on the function of Mrp3. In its absence, sufficient hepatic accumulation occurs to redirect some of the APAP-GLUC to bile. This altered disposition in Mrp3-/- mice is associated with reduced hepatotoxicity.
Manautou
José E
JE
Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT, USA.
de Waart
Dirk R
DR
Kunne
Cindy
C
Zelcer
Noam
N
Goedken
Michael
M
Borst
Piet
P
Elferink
Ronald Oude
RO
D000082:Acetaminophen / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000506:poisoning; D018712:Analgesics, Non-Narcotic / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000506:poisoning; D000818:Animals; D001646:Bile / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000172:deficiency*; D009994:Osmolar Concentration; D010477:Perfusion
D000082:Acetaminophen; D018712:Analgesics, Non-Narcotic; D005978:Glutathione; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C114462:multidrug resistance-associated protein 3