TY - JOUR
T1 - The basis for strain-dependent rat aldehyde dehydrogenase 1A7 (ALDH1A7) gene expression
AU - Touloupi, Katerina
AU - Küblbeck, Jenni
AU - Magklara, Angeliki
AU - Molnár, Ferdinand
AU - Reinisalo, Mika
AU - Konstandi, Maria
AU - Honkakoski, Paavo
AU - Pappas, Periklis
N1 - Funding Information:
This work was supported by the Greek Ministry of Education, Research and Religious Affairs-Herakleitos (K.T., A.M., M.K., P.P.) and by the Academy of Finland (J.K, F.M., M.R., P.H). This study is dedicated to Prof. Marios Marselos on his discovery of the strain difference and subsequent work on ALDH induction in the Ioannina rat strains. This work was supported by the Greek Ministry of Education, Research and Religious Affairs-Herakleitos (K.T., A.M., M.K., P.P.) and by the Academy of Finland (J.K, F.M., M.R., P.H). The ALDH1A7 promoter sequences have been submitted to the Genbank with accession numbers MK814117 (RR) and MK814118 (rr). We thank Ms. Lea Pirskanen for her expert help in molecular biology assays.
Funding Information:
This work was supported by the Greek Ministry of Education, Research and Religious Affairs-Herakleitos (K.T., A.M., M.K., P.P.) and by the Academy of Finland (J.K, F.M., M.R., P.H). This study is dedicated to Prof. Marios Marselos on his discovery of the strain difference and subsequent work on ALDH induction in the Ioannina rat strains. This work was supported by the Greek Ministry of Education, Research and Religious Affairs-Herakleitos (K.T., A.M., M.K., P.P.) and by the Academy of Finland (J.K, F.M., M.R., P.H). The ALDH1A7 promoter sequences have been submitted to the Genbank with accession numbers MK814117 (RR) and MK814118 (rr). https://doi.org/10.1124/mol.119.117424. s This article has supplemental material available at molpharm. aspetjournals.org.
Publisher Copyright:
Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics.
PY - 2019/11
Y1 - 2019/11
N2 - 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, whereas the nonresponsive rr 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 RR strain but negligibly in the rr 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 rr 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.
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, whereas the nonresponsive rr 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 RR strain but negligibly in the rr 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 rr 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.
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U2 - 10.1124/mol.119.117424
DO - 10.1124/mol.119.117424
M3 - Article
C2 - 31575620
AN - SCOPUS:85073183754
SN - 0026-895X
VL - 96
SP - 655
EP - 663
JO - Molecular Pharmacology
JF - Molecular Pharmacology
IS - 5
ER -