Regulation of mouse organic anion-transporting polypeptides (Oatps) in liver by prototypical microsomal enzyme inducers that activate distinct transcription factor pathways.
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 aryl hydrocarbon receptor (AhR), constitutive androstane receptor (CAR), pregnane X receptor (PXR), peroxisome proliferator-activated receptor alpha (PPARalpha), and nuclear factor erythroid 2-related factor 2 (Nrf2). However, regulation of organic anion-transporting polypeptide (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, PPARalpha, 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, PPARalpha ligands increased Cyp4A14, and Nrf2 activators induced NAD(P)H:quinone oxidoreductase 1. AhR ligands (2,3,7,8-tetrachlorodibenzo-p-dioxin, polychlorinated biphenyl 126, and beta-naphthoflavone) increased Oatp2b1 and 3a1 mRNA expression in liver. CAR activators [phenobarbital, 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene, and diallyl sulfide] decreased Oatp1a1 mRNA expression. Two PXR ligands [pregnenolone-16alpha-carbonitrile (PCN) and spironolactone] increased Oatp1a4 mRNA expression in liver, whereas PXR ligands (PCN, spironolactone, and dexamethasone) and PPARalpha 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.
Cheng
Xingguo
X
Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA.
Maher
Jonathan
J
Dieter
Matthew Z
MZ
Klaassen
Curtis D
CD
D000818:Animals; D000090702:Constitutive Androstane Receptor; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D020536:Enzyme Activators / Q000494:pharmacology*; D004790:Enzyme Induction; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D008099:Liver / Q000201:enzymology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000096:biosynthesis*; D027361:Organic Anion Transporters / Q000235:genetics / Q000378:metabolism*; D047493:PPAR alpha / Q000378:metabolism; D000077297:Pregnane X Receptor; D012333:RNA, Messenger / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D011987:Receptors, Steroid / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
D000090702:Constitutive Androstane Receptor; D020536:Enzyme Activators; D027361:Organic Anion Transporters; D047493:PPAR alpha; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors; D003577:Cytochrome P-450 Enzyme System; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human