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Vol. 30, Issue 8, 918-923, August 2002
Division of Drug Delivery and Disposition, School of Pharmacy,
University of North Carolina, Chapel Hill, North Carolina (H.X.,
K.L.R.B.); and Pharmacogenetics Section, Laboratory of Reproductive and
Developmental Toxicology, National Institute of Environmental Health
Sciences, National Institutes of Health, Research Triangle Park, North
Carolina (K.Y., M.N.)
Phenobarbital (PB) induces the hepatic organic anion
transporter, Mrp3. The present study tested the hypothesis that Mrp3 induction by PB is mediated by the constitutive androstane receptor (CAR). PB induction of Mrp3 and CYP2B was examined in lean and obese
Zucker rats, male and female Wistar Kyoto (WKY) rats, HepG2 and mouse
CAR-expressing HepG2 (g2car-3) cells; HepG2 and g2car-3 cells also were
treated with 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP). In
obese Zucker rat livers, total and nuclear CAR levels were markedly
lower compared with lean rat livers, which correlated with the poor
induction of CYP2B1/2 by PB in obese Zucker rats. Mrp3 induction by PB
also was impaired in obese Zucker rat livers. Induction of Mrp3 by PB
was similar in male and female WKY rat livers, despite the fact that
CAR protein levels were significantly lower in female relative to male
WKY rat livers. MRP3 levels in both HepG2 and g2car-3 cells were
induced to a similar extent in the two cell lines by PB but not by
TCPOBOP. In contrast, CYP2B6 levels were measurable and induced by
TCPOBOP only in g2car-3 cells. In conclusion, data from WKY rats and
HepG2 cells suggest that CAR does not play a key role in PB induction
of Mrp3. Impaired induction of Mrp3 by PB in obese Zucker rats is not
due solely to CAR deficiency. Interestingly, differences in the
constitutive levels of Mrp3 were observed between obese and lean Zucker
rats and between male and female WKY rats.
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