PT  - JOURNAL ARTICLE
AU  - Katerina Touloupi
AU  - Jenni Kublbeck
AU  - Angeliki Magklara
AU  - Ferdinand Molnar
AU  - Mika Reinisalo
AU  - Maria Konstandi
AU  - Paavo Honkakoski
AU  - Periklis Pappas
TI  - The basis for strain-dependent rat aldehyde dehydrogenase 1A7 (ALDH1A7) gene expression
AID  - 10.1124/mol.119.117424
DP  - 2019 Jan 01
TA  - Molecular Pharmacology
PG  - mol.119.117424
4099  - http://molpharm.aspetjournals.org/content/early/2019/10/01/mol.119.117424.short
4100  - http://molpharm.aspetjournals.org/content/early/2019/10/01/mol.119.117424.full
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.