Abstract
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.
Footnotes
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This work was supported by National Institutes of Health Grant GM41935. K.Y. was supported by research fellowships from the Japanese Society for the Promotion of Science. This work was presented in part at the American Association of Pharmaceutical Scientists Annual Meeting, 2001 Oct 21–25, in Denver, CO and was submitted to the Graduate School of the University of North Carolina in partial fulfillment of requirements for the Doctor of Philosophy degree in Pharmaceutical Sciences (H.X.).
- Abbreviations used are::
- Mrp3/MRP3
- multidrug resistance-associated protein 3
- PB
- phenobarbital
- P450
- cytochrome P450
- CAR
- constitutive androstane receptor
- PXR
- pregnane X receptor
- WKY
- Wistar Kyoto
- g2car-3
- mouse CAR-expressing HepG2
- RT-PCR
- reverse transcription-polymerase chain reaction
- TCPOBOP
- 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene
- RXR
- retinoid X receptor
- NOR
- nuclear orphan receptor
- FXR
- farnesoid X receptor
- APx
- activator protein 1, 2, or 3
- PCN
- pregnenolone 16α-carbonitrile
- Received February 12, 2002.
- Accepted May 10, 2002.
- U.S. Government
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Role of Constitutive Androstane Receptor in the In Vivo Induction of Mrp3 and CYP2B1/2 by Phenobarbital
