ToxSci Advance Access originally published online on November 12, 2007
Toxicological Sciences 2008 101(1):51-64; doi:10.1093/toxsci/kfm280
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Tissue Distribution, Ontogeny, and Regulation of Aldehyde Dehydrogenase (Aldh) Enzymes mRNA by Prototypical Microsomal Enzyme Inducers in Mice
Kansas Life Sciences Innovation Center, University of Kansas Medical Center, Kansas City, Kansas 66160
1 To whom correspondence should be addressed at Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160. Fax: (913) 588-7714. E-mail: cklaasse{at}kumc.edu.
Received July 11, 2007; accepted September 24, 2007
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Abstract |
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Aldehyde dehydrogenases (Aldhs) are a group of nicotinamide adenine dinucleotide phosphate–dependent enzymes that catalyze the oxidation of a wide spectrum of aldehydes to carboxylic acids. Tissue distribution and developmental changes in the expression of the messenger RNA (mRNA) of 15 Aldh enzymes were quantified in male and female mice tissues using the branched DNA signal amplification assay. Furthermore, the regulation of the mRNA expression of Aldhs by 15 typical microsomal enzyme inducers (MEIs) was studied. Aldh1a1 mRNA expression was highest in ovary; 1a2 in testis; 1a3 in placenta; 1a7 in lung; 1b1 in small intestine; 2 in liver; 3a1 in stomach; 3a2 and 3b1 expression was ubiquitous; 4a1, 6a1, 7a1, and 8a1 in liver and kidney; 9a1 in liver, kidney, and small intestine; and 18a1 in ovary and small intestine. mRNAs of different Aldh enzymes were detected at lower levels in fetuses than adult mice and gradually increased after birth to reach adult levels between 15 and 45 days of age, when the gender difference began to appear. Aromatic hydrocarbon receptor (AhR) ligands induced the liver mRNA expression of Aldh1a7, 1b1, and 3a1, constitutive androstane receptor (CAR) activators induced Aldh1a1 and 1a7, whereas pregnane X receptor (PXR) ligands and NF-E2 related factor 2 (Nrf2) activators induced Aldh1a1, 1a7, and 1b1. Peroxisome proliferator activator receptor alpha (PPAR
) ligands induced the mRNA expression in liver of almost all Aldhs. The Aldh organ-specific distribution may be important in elucidating their role in metabolism, elimination, and organ-specific toxicity of xenobiotics. Finally, in contrast to other phase-I metabolic enzymes such as CYP450 enzymes, Aldh mRNA expression seems to be generally insensitive to typical microsomal inducers except PPAR ligands.
Key Words: developmental toxicity; postnatal; reproductive and developmental toxicology; metabolism; biotransformation and toxicokinetics; transcription factors; gene expression/regulation.