RT Journal Article SR Electronic T1 The basis for strain-dependent rat aldehyde dehydrogenase 1A7 (ALDH1A7) gene expression JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP mol.119.117424 DO 10.1124/mol.119.117424 A1 Katerina Touloupi A1 Jenni Kublbeck A1 Angeliki Magklara A1 Ferdinand Molnar A1 Mika Reinisalo A1 Maria Konstandi A1 Paavo Honkakoski A1 Periklis Pappas YR 2019 UL http://molpharm.aspetjournals.org/content/early/2019/10/01/mol.119.117424.abstract AB Aldehyde hydrogenases (ALDHs) belong to a large gene family involved in oxidation of both endogenous and exogenous compounds in mammalian tissues. Among ALDHs, the rat ALDH1A7 gene displays a curious strain-dependence in phenobarbital (PB)-induced hepatic expression: the responsive RR strains exhibit induction of both ALDH1A7 and CYP2B mRNAs and activities while the non-responsive rr strains show induction of CYP2B only. Here, we investigated the responsiveness of ALDH1A1, ALDH1A7, CYP2B1 and CYP3A23 genes to prototypical CYP inducers, expression of nuclear receptors CAR and PXR, and structure of the ALDH1A7 promoter in both rat strains. ALHD1A1 and ALDH1A7 mRNA, associated protein and activity were strongly induced by PB and modestly by pregnenolone 16a-carbonitrile in the RR strain but negligibly in the rr strain. Reporter gene and chromatin immunoprecipitation assays indicated that the loss of ALDH1A7 inducibility in the rr strain is profoundly linked with a 16-bp deletion in the proximal promoter and inability of the upstream DNA sequences to recruit CAR-retinoid X receptor heterodimers.SIGNIFICANCE STATEMENT Genetic variation in rat ALDH1A7 promoter sequences underlie the large strain-dependent differences in expression and inducibility by phenobarbital of the aldehyde dehydrogenase activity. This has implications for the design and interpretation of pharmacological and toxicological studies on the effects and disposition of aldehydes.