PMID- 24799397
OWN - NLM
STAT- MEDLINE
DCOM- 20150105
LR  - 20240321
IS  - 1521-009X (Electronic)
IS  - 0090-9556 (Print)
IS  - 0090-9556 (Linking)
VI  - 42
IP  - 7
DP  - 2014 Jul
TI  - Hepatocellular exposure of troglitazone metabolites in rat sandwich-cultured 
      hepatocytes lacking Bcrp and Mrp2: interplay between formation and excretion.
PG  - 1219-26
LID - 10.1124/dmd.114.057190 [doi]
AB  - Inhibition of bile acid transport by troglitazone (TGZ) and its major metabolite, 
      TGZ sulfate (TS), may lead to hepatocellular accumulation of toxic bile acids; TS 
      accumulation and hepatotoxicity may be associated with impaired TS biliary 
      excretion. This study evaluated the impact of impaired transport of breast cancer 
      resistance protein (Bcrp) and multidrug resistance-associated protein 2 (Mrp2) on 
      the hepatobiliary disposition of generated metabolites, TS and TGZ glucuronide 
      (TG). Sandwich-cultured hepatocytes (SCH) from Mrp2-deficient (TR(-)) rats in 
      combination with Bcrp knockdown using RNA interference were employed. The biliary 
      excretion index (BEI) of generated TS was not significantly altered by impaired 
      Bcrp (20.9 to 21.1%) and/or Mrp2 function (24.4% and 17.5% in WT and TR(-) rat 
      SCH, respectively). Thus, loss-of-function of Mrp2 and/or Bcrp do not appear to 
      be risk factors for increased hepatocellular TS accumulation in rats, potentially 
      because of a compensatory transporter(s) that excretes TS into bile. Further 
      investigations revealed that the compensatory TS biliary transporter was not the 
      bile salt export pump (Bsep) or P-glycoprotein (P-gp). Interestingly, TGZ 
      sulfation was significantly decreased in TR(-) compared with WT rat SCH (total 
      recovery: 2.8 versus 5.0% of TGZ dose), resulting in decreased hepatocellular TS 
      accumulation, even though sulfotransferase activity in TR(-) rat hepatocyte S9 
      fraction was similar. Hepatocellular TG accumulation was significantly increased 
      in TR(-) compared with WT rat SCH due to increased glucuronidation and negligible 
      TG biliary excretion. These data emphasize that the interplay between metabolite 
      formation and excretion determines hepatocellular exposure to generated 
      metabolites such as TS and TG.
CI  - Copyright (c) 2014 by The American Society for Pharmacology and Experimental 
      Therapeutics.
FAU - Yang, Kyunghee
AU  - Yang K
AD  - Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of 
      Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North 
      Carolina.
FAU - Brouwer, Kim L R
AU  - Brouwer KL
AD  - Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of 
      Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North 
      Carolina kbrouwer@unc.edu.
LA  - eng
GR  - R01 GM041935/GM/NIGMS NIH HHS/United States
PT  - Journal Article
DEP - 20140505
PL  - United States
TA  - Drug Metab Dispos
JT  - Drug metabolism and disposition: the biological fate of chemicals
JID - 9421550
RN  - 0 (ATP Binding Cassette Transporter, Subfamily G, Member 2)
RN  - 0 (ATP-Binding Cassette Transporters)
RN  - 0 (Abcc2 protein, rat)
RN  - 0 (Abcg2 protein, rat)
RN  - 0 (Chromans)
RN  - 0 (Hypoglycemic Agents)
RN  - 0 (Thiazolidinediones)
RN  - I66ZZ0ZN0E (Troglitazone)
SB  - IM
MH  - ATP Binding Cassette Transporter, Subfamily G, Member 2
MH  - ATP-Binding Cassette Transporters/*metabolism
MH  - Animals
MH  - Cells, Cultured
MH  - Chromans/*metabolism
MH  - Hepatocytes/*drug effects/metabolism
MH  - Hypoglycemic Agents/*metabolism
MH  - Male
MH  - Rats
MH  - Rats, Wistar
MH  - Thiazolidinediones/*metabolism
MH  - Troglitazone
PMC - PMC4053994
EDAT- 2014/05/07 06:00
MHDA- 2015/01/06 06:00
PMCR- 2015/07/01
CRDT- 2014/05/07 06:00
PHST- 2014/05/07 06:00 [entrez]
PHST- 2014/05/07 06:00 [pubmed]
PHST- 2015/01/06 06:00 [medline]
PHST- 2015/07/01 00:00 [pmc-release]
AID - dmd.114.057190 [pii]
AID - DMD_057190 [pii]
AID - 10.1124/dmd.114.057190 [doi]
PST - ppublish
SO  - Drug Metab Dispos. 2014 Jul;42(7):1219-26. doi: 10.1124/dmd.114.057190. Epub 2014 
      May 5.