Abstract
The transcription factors AhR, CAR, PXR, PPARα, and Nrf2 regulate genes encoding drug metabolizing enzymes and transporters in livers of mice following chemical activation. However, the specificity of their transcriptional regulation has not been determined systematically in vivo. The purpose of this study was to identify genes encoding drug metabolizing enzymes and transporters altered by chemical activators in a transcription factor-dependent manner using wild-type and transcription factor-null mice. Chemical activators were administered ip to mice once daily for 4 days. Livers were collected 24h after the final dose, and total RNA was isolated for mRNA quantification of cytochrome P450s (Cyp), NAD(P)H quinone oxidoreductase 1 (Nqo1), aldehyde dehydrogenases (Aldhs), glutathione-S-transferases (Gsts), sulfotransferases (Sults), UDP-glucuronosyltransferases (Ugts), organic anion transporting polypeptides (Oatps), and multidrug resistance-associated proteins (Mrps). Pharmacological activation of each transcription factor leads to mRNA induction of drug metabolic and transport genes in livers of male and female wild-type mice, but no change in null mice: AhR (Cyp1a2, Nqo1, Aldh7a1, Ugt1a1, 1a6, 1a9, 2b35, Sult5a1, Gstm3, Mrp4), CAR (Cyp2b10, Aldh1a1, 1a7, Ugt1a1, 2b34, Sult1e1, 3a1, 5a1, Papps2, Gstt1, a1, a4, m1-4, Mrp2-4), PXR (Cyp3a11, Ugt1a1, 1a5, 1a9, Gsta1, m1-m3, Oatp1a4, Mrp3), PPARα (Cyp4a14, Aldh1a1, mGst3, Gstm4, Mrp4), and Nrf2 (Nqo1, Aldh1a1, Gsta1, a4, m1-m4, mGst3, Mrp3-4). Collectively, these data reveal transcription factor specificity and overlap in regulating hepatic drug disposition genes by chemical activators. Coordinated regulation of phase-I, -II, and transport genes by activators of transcription factors can have implications in development of pharmaceuticals as well as risk assessment of environmental contaminants.
- ABC transporters
- glutathione transferases
- hepatic transport
- hepatic uptake
- hepatocytes
- NAD(P)H-quinone oxidoreductase
- nuclear receptors
- organic anion transport
- sulfotransferases
- UDP glucuronyltransferases
- Received February 17, 2012.
- Accepted April 11, 2012.
- The American Society for Pharmacology and Experimental Therapeutics