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Received for publication February 2, 2005.
Revised April 15, 2005.
Accepted for publication May 25, 2005.
Drug metabolizing enzymes and transporters are key factors that affect disposition of xenobiotics. Phase-I enzyme induction by classes of microsomal enzyme inducers occurs via activation of transcription factors such as AhR, CAR, PXR, PPAR
, and Nrf2. However, regulation of Oatp uptake transporters by these factors is poorly understood. Hepatic Oatp uptake of some chemicals must occur prior to biotransformation, thus we hypothesize that expression of Oatps and biotransformation enzymes is coordinately regulated in liver. In the present study, the effects of known chemical activators of AhR, CAR, PXR, PPAR, and Nrf2 on the hepatic mRNA expression of mouse Oatps and drug metabolizing enzymes were quantified by the branched DNA assay. All chemicals increased the expression of their well-characterized target drug metabolizing enzymes: AhR ligands increased Cyp1A1; CAR activators increased Cyp2B10; PXR ligands increased Cyp3A11; PPAR ligands increased Cyp4A14; and Nrf2 activators induced NAD(P)H:quinone oxidoreductase (Nqo)1. AhR ligands (TCDD, polychlorinated biphenyl 126, and 
-naphthoflavone) increased Oatp2b1 and 3a1 mRNA expression in liver. CAR activators (phenobarbital, TCPOBOP, and diallyl sulfide) decreased Oatp1a1 mRNA expression. Two PXR ligands (PCN and spironolactone) increased Oatp1a4 mRNA expression in liver, whereas PXR ligands (PCN, spironolactone, and dexamethasone) and PPAR ligands (clofibrate, ciprofibrate, and diethylhexylphthalate) decreased Oatp1a1, 1b2, 2a1, and 2b1 mRNA expression in liver. Nrf2 activators (oltipraz, ethoxyquin, and butylated hydroxyanisole) down-regulated Oatp1a1, but up-regulated Oatp2b1 mRNA expression. Therefore, only a few transcription factor activators increased Oatp expression, and surprisingly, many decreased Oatp expression.
Key words:
CYP gene regulation, gene regulation, hepatic transport, hepatic uptake, transcriptional regulation
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