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The Basis for Strain-Dependent Rat Aldehyde Dehydrogenase 1A7 (ALDH1A7) Gene Expression
Katerina Touloupi1, Jenni Küblbeck1, Angeliki Magklara1
1Departments of Pharmacology (K.T., M.K., P.P.) and Clinical Chemistry (A.M.), Faculty of Medicine, School of Health Sciences, University of Ioannina, and Department of Biomedical Research, Institute of Molecular Biology and Biotechnology, Foundation of Research and Technology (A.M.), Ioannina, Greece; School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland (J.K., F.M., M.R., P.H.);Department of Biology, School of Science and Technology, Nazarbayev University, Nur-Sultan City, Kazakhstan (F.M.); Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (P.H.).
Abstract:
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 strains exhibit induction of both ALDH1A7 and CYP2B mRNAs and activities, whereas the nonresponsive strains show induction of CYP2B only. Here, we investigated the responsiveness of ALDH1A1, ALDH1A7, CYP2B1, and CYP3A23 genes to prototypical P450 inducers, expression of nuclear receptors CAR and pregnane X receptor, and structure of the ALDH1A7 promoter in both rat strains. ALDH1A7 mRNA, associated protein and activity were strongly induced by PB and modestly induced by pregnenolone 16α-carbonitrile in the strain but negligibly in the strain, whereas induction of ALDH1A1 and P450 mRNAs was similar between the strains. Reporter gene and chromatin immunoprecipitation assays indicated that the loss of ALDH1A7 inducibility in the strain is profoundly linked with a 16-base pair deletion in the proximal promoter and inability of the upstream DNA sequences to recruit constitutive androstane receptor-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 finding has implications for the design and interpretation of pharmacological and toxicological studies on the effects and disposition of aldehydes.
