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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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONSUPPLEMENTARY DATAFUNDINGREFERENCES |
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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.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONSUPPLEMENTARY DATAFUNDINGREFERENCES |
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Aldehyde dehydrogenases (Aldhs) are a group of NAD(P)+ (nicotinamide adenine dinucleotide phosphate)–dependent enzymes that catalyze the irreversible oxidation of a wide spectrum of endogenous and exogenous aldehydes to their corresponding carboxylic acids. Most Aldh isozymes prefer NAD+ over NADP+ as a cofactor (Yoshida et al., 1998
). Aldhs exhibit broad substrate specificity and many of them can oxidize aliphatic and aromatic aldehydes. Endogenous aldehydes are formed during metabolism of various alcohols, amino acids, biogenic amines, vitamins, steroids, and lipids. Aldehydes formed during oxidative stress are long-lived molecules and potent electrophiles that interact with cellular constituents, including proteins and nucleic acids (Esterbauer et al., 1991). Therefore, Aldhs are considered to be detoxifying enzymes. In some cases, Aldhs serve structural rather than enzymatic roles as major components of lens and corneal proteins (Lee et al., 1993).
The Aldh gene superfamily members share at least 15% amino acid similarity. Aldh isozymes that share more than 40% amino acid identity are grouped in one family. One exception to this nomenclature rule is Aldh2, which preserved its old nomenclature due to the very extensive clinical work on correlations of this gene with alcohol toxicity and addiction. Aldh1a1 and 2 are 68% similar and should be members of the same family (Vasiliou et al., 1999).
The cytosolic class-1 Aldhs have been thoroughly studied because of their role in retinoic acid (RA) biosynthesis. RA is a potent modulator of gene expression and tissue differentiation during development and postnatally, by serving as a ligand for several nuclear RA receptors and retinoid X receptors (Molotkov and Duester, 2003). Yet, excessive RA causes toxicity, both to the embryo and postnatally. RA is produced in a two-step reaction starting with the oxidation of retinol (vitamin A) by alcohol dehydrogenases, followed by the irreversible conversion of retinal to RA by different retinal dehydrogenases (RAldhs) (Duester, 2001).
Aldh1a1 (RAldh1) has a substrate preference for the aldehyde products of lipid peroxidation, such as the medium-chain aliphatic aldehydes, 4-hydroxynenonal (4HNE), and malondialdehyde, as well as retinaldehyde. This enzyme also detoxifies cyclophosphamide, which belongs to the widely used oxazaphosphorine family of anticancer drugs (Manthey et al., 1990). Cancer cells acquire resistance to these drugs due to the upregulation of Aldh1a1 as well as Aldh3a1 expression in tumors (Sreerama and Sladek, 1997; Tsukamoto et al., 1998). Aldh1a1 is a major soluble constituent of the eye lens and may play a role in detoxification of peroxidic aldehydes produced by ultraviolet light absorption (King and Holmes, 1997).
Aldh1a2 (RAldh2) exhibits the highest substrate specificity and catalytic efficiency for retinal oxidation to RA (Duester, 2001; Maly et al., 2003). Aldh2a1-null mice exhibit a lethal phenotype with embryos dying and failing to produce RA at E7.5–8.5. Embryos can be partially rescued by maternal RA administration (Niederreither et al., 1999). Therefore, it was suggested that Aldh1a2 is the predominant regulator of RA synthesis in mouse embryos of the midgestational stages, whereas Aldh1a1 and 1a3 isozymes dominate in late stage embryonic development (Hsu et al., 2000).
Both Aldh1a2 and 1a3 (RAldh3) are more effective and selective in retinaldehyde oxidation than Aldh1a1 (Niederreither et al., 1997). Aldh1a3-null mice die within 10 h of birth due to defects in nasal development (Dupe et al., 2003). All defects can be reversed by RA administration (Dupe et al., 2003).
RA exhibits a concentration gradient in embryonic tissues with some tissues containing more RA than others, which is necessary for the overall control of embryonic development by retinoids. Raldhs have different activities in RA synthesis, therefore their age- and tissue-specific distribution is responsible for establishing the aforementioned RA gradient in embryonic tissues (Haselbeck et al., 1999). In this respect, Aldh1a2 might be the major RA-synthesizing isozyme involved in early embryogenesis, whereas Aldh1a1 and 1a3 isozymes are more important in late stage embryonic development (Dupe et al., 2003).
Aldh1a7 is induced by phenobarbital (PB) treatment in rats, resulting in up to a 10-fold increase in liver supernatant Aldh activity (Deitrich, 1971), and therefore is referred to as Aldh-PB or PB-inducible Aldh. Aldh1a7 amino acid sequence is highly identical to Aldh1a1 and its identity is commonly interchanged with 1a1 (Kathmann and Lipsky, 1997; Kathmann et al., 2000; Marselos et al., 1987). They differ in expression patterns, substrate preferences, and sensitivities to disulfiram inhibition. Most importantly, Aldh1a7 cannot catalyze the oxidation of retinal to RA, and therefore does not belong to the RAldhs isozymes (Hsu et al., 1999; Marselos et al., 1987).
Aldh2 is a mitochondrial enzyme of special clinical importance because of its major role in alcohol metabolism. Aldh2 is the major enzyme for the disposal of acetaldehyde generated during metabolism of ethanol (Thomasson et al., 1991). A point mutation in Aldh2 is responsible for the alcohol flushing syndrome in orientals caused by elevated blood levels of acetaldehyde (Thomasson et al., 1991).
Aldh3 class is of considerable interest because of its close association with cancer. The cytosolic Aldh3A1 isozyme oxidizes medium-chain lipid and aromatic aldehydes such as hexanal and benzaldehyde, utilizing NADP+ rather than NAD+ as a cofactor (Vasiliou and Pappa, 2000). Aldh3a1 is constitutively expressed at low or undetectable levels in the normal liver, whereas it is highly expressed in hepatoma and other cancerous cells, with its expression in direct correlation with the degree of tumor deviation (Canuto et al., 1994). The increase in Aldh3a1 activity is evident in approximately 50% of liver carcinoma patients (Chang et al., 1998). Aldhs, especially Aldh3a1, defend the cell against the cytotoxic and cytostatic aldehyde products of lipid peroxidation, such as 4HNE (Chang et al., 1998). Therefore, the increased Aldh3a1 expression of the carcinoma cells are critical for their growth (Canuto et al., 1999). Furthermore, the increase of Aldh1a1 and 3a1 expression is potentially responsible for the acquired tumor cells resistance to some anticancer drugs (Rekha et al., 1994).
Aldh3a2 is a microsomal enzyme with high activity for oxidation of medium-chain aliphatic aldehydes (fatty aldehydes derived from several 16–18 carbon lipids; Rizzo et al., 2001). Therefore, Aldh3a2 is referred to as fatty aldehyde Aldh. Various mutations in Aldh3a2 cause an inherited disease called Sjögren–Larsson syndrome (SLS). SLS is characterized by ichthyosis, spasticity, preterm birth, and various neurological problems (De Laurenzi et al., 1996).
Aldh4a1, also known as pyrroline-5-carboxylate (P5C) dehydrogenase, is a mitochondrial enzyme that catalyzes the conversion of P5C, derived either from proline or ornithine, to glutamate (Hu et al., 1996). The preferred substrates of Aldh4a1 are glutamic 
-semialdehydes, succinic, glutaric, and adipic semialdehydes (Forte-McRobbie and Pietruszko, 1986). Aldh4a1 deficiency causes type II-hyperprolinemia, an autosomal recessive disorder associated with neurological manifestations, including seizures and mental retardation (Valle et al., 1974; Yoshida et al., 1998).
The mitochondrial Aldh6a1 is the only CoA-dependent Aldh. Aldh6a1 is involved in the catabolic pathways of valine and pyrimidine by catalyzing the oxidative decarboxylation of malonate and methylmalonate semialdehydes to acetyl and propionyl-CoA, respectively (Kedishvili et al., 1992, 2000). Therefore, Aldh6a1 is also known as methylmalonate semialdehyde dehydrogenase. Aldh6a1 deficiency causes defects in valine catabolism and also is associated with developmental delays (Chambliss et al., 1995).
The cytosolic Aldh7a1 was found in rats and humans because of the high homology to the protein antiquetin in the green garden pea (Lee et al., 1994; Skvorak et al., 1997), which is upregulated when the plant is dehydrated. Aldh7a1 is thought to contribute in balancing the hydrostatic pressure inside the ear. A mutation in Aldh7a1 has been suggested to contribute in the Meniere disease (MD), an inner ear disorder characterized by tinnitus, vertigo, and hearing loss (Lynch et al., 2002).
Aldh8a1 is the fourth member in the RAldh isozymes, therefore it is also known as Raldh4. Compared with other Raldhs, Aldh8a1 is the only isozyme to show preference for 9-cis-retinal versus all-trans-retinal (Lin et al., 2003).
Aldh9a1 is a cytosolic enzyme with a high activity for oxidation of 4-aminobutyraldehyde to the inhibitory neurotransmitter -aminobutyric acid (Kikonyogo and Pietruszko, 1996), betaine aldehyde to betaine, which can serve as a methyl donor for biosynthesis of methionine, and has also been proposed to be involved in the regulation of osmolarity in kidney (Grunewald and Eckstein, 1995). Aldh9a1 also has been identified as -trimethylaminobutyraldehyde dehydrogenase involved in carnitine biosynthesis (Vaz et al., 2000).
The mitochondrial Aldh18a1, also known as P5C synthase (P5CS), is one of seven enzymes that operate synchronously in arginine and proline synthesis from their endogenous precursor glutamate (Hu et al., 1999). Aldh18a1 catalyzes the conversion of L-glutamate to glutamic -semialdehyde (Hu et al., 1999). A human genetic disease caused by a deficient P5CS is associated with skin hyperelasticity, cataracts, and mental retardation (Aral et al., 1996).
Early studies addressed tissue distribution, ontogenic expression, and induction of Aldh isozymes by a wide variety of chemical inducers. Many of these studies reported different results due to the various methodologies used, ranging from messenger RNA (mRNA) and protein expression to enzymatic activity measurement. Furthermore, many studies have reported significant induction of Aldhs by chemical inducers in vitro, which were absent in vivo. In the present study, the tissue distribution, gender differences, and ontogenic expression of 15 Aldh isozymes in mice were determined. Most studies in the literature concerning the tissue distribution of Aldhs have been limited to a few tissues, and were not quantitative. The Aldh organ-specific distribution may be important in elucidating their role in metabolism, elimination, and organ-specific toxicity of xenobiotics. Furthermore, the present study addresses the regulation of Aldh isozymes by five groups of prototypical MEIs in male mice. These five groups represent common ligand-activated transcription factors pathways known to be involved in the induction of phase-I and -II enzymes, and comprise AhR, PXR, CAR, peroxisome proliferator activator receptor alpha (PPAR) and Nrf2 ligands or activators.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONSUPPLEMENTARY DATAFUNDINGREFERENCES |
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Chemicals.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) was a gift from Dr Karl Rozman (University of Kansas Medical Center, KS). Oltipraz (OPZ) was a gift from Dr R. Lubet (National Cancer Institute, Bethesda, MD). Polychlorinated biphenyl 126 (PCB126) was obtained from AccuStandard (New Haven, CT). β-Naphthoflavone (BNF), diallyl sulfide (DAS), clofibric acid (CLOF), di-(2-ethylhexyl) phthalate (DEHP), ethoxyquin (EXQ), dexamethasone (DEX), pregnenolone-16
-carbonitrile (PCN), ciprofibrate (CIPRO), butylated hydroxyanisole (BHA), spironolactone (SPR), PB, and 1,4-bis[2-(3,5-dichloropuridyloxy)]benzene (TCPOBOP) were purchased from Sigma-Aldrich Co. (St Louis, MO). RNA-Bee was obtained from Tel-Test, Inc. (Friendswood, TX).
Animals.
Eight-week-old male and female C57BL/6 mice were purchased from Charles River Laboratories, Inc. (Wilmington, MA). Animals were housed in a temperature-, light-, and humidity-controlled environment. Mice were fed Laboratory Rodent Chow W (Harlan Teklad, Madison, WI) ad libitum. Tissues were removed from five mice of each gender, frozen in liquid nitrogen, and stored at –80°C until mRNA isolation. For the ontogeny study, livers, and kidneys from male and female mice were collected at –2, 0, 5, 10, 15, 22, 30, and 45 days of age (n = 5/gender/age). Male and female pups were pooled at age –2, because it was difficult to determine their gender.
Treatment with MEIs.
Approximately 8-week-old male C57BL/6 mice were purchased from Charles River Laboratories, Inc. and were dosed with MEIs (n = 5/treatment). The chemicals, route of administration, dosing regimen, and vehicles are indicated in Table 1. After dosing each day for 4 days with the MEIs, livers were removed on day 5, snap-frozen in liquid nitrogen, and stored at –80°C. The dose and dosing regimen of these compounds were previously shown to induce the corresponding target genes in mice, namely Cyp1A1 for AhR ligands, Cyp2B10 for CAR activators, Cyp3A11 for PXR ligands, Cyp4A14 for PPAR ligands, and Nqo1 for Nrf2 activators (Maher et al., 2005).
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Total RNA isolation.
Total RNA was isolated using RNA-Bee reagent (Tel-Test, Inc.) according to the manufacturer's protocol. Total RNA concentrations were determined spectrophotometrically at 260 nm. One microgram per microliter solutions were prepared from the stock RNA solution by dilution with diethyl pyrocarbonate-treated deionized water. Integrity of RNA samples was evaluated visually using agarose gel electrophoresis. Samples were then visualized under ultraviolet light by ethidium bromide fluorescence.
Branched DNA signal amplification analysis.
The mRNA of each Aldh in mouse tissues was quantified using the branched DNA signal amplification (bDNA) assay (Quantigene bDNA signal amplification kit; Panomics, Inc., Fremont, CA) with modifications (Hartley and Klaassen, 2000). Gene sequences of interest were accessed from GenBank. Target sequences were analyzed using ProbeDesigner software v1.0 (Panomics, Inc.) to design oligonucleotide probe sets (capture, label, and blocker probes). All probes were designed with a melting temperature of 63°C, enabling hybridization conditions to be held constant (i.e., 53°C) during each hybridization step. Each developed probe was submitted to the National Center of Biotechnology Information (NCBI, Bethesda, MD) by the basic local alignment search tool (BLASTn) to ensure minimal cross-reactivity with other known mouse sequences. Oligonucleotides with a high degree of similarity (> 80%) to other mouse gene transcripts were eliminated from the design. The sequences and functions of the probe sets are listed in Table 2 as Supplementary Data.
Total RNA (1 µg/µl; 10 µl/well) was added to each well of a 96-well plate containing 50 µl of each diluted probe set. RNA was allowed to hybridize with the probe sets overnight at 53°C. Subsequent hybridization steps were carried out according to the manufacturer's protocol, and luminescence was quantified with a Quantiplex 320 bDNA luminometer interfaced with Quantiplex Data Management software v5.02. Data are presented as relative light units (RLU) per 10 µg of total RNA.
Statistical analysis.
Statistical differences were determined using student's t test with significance set at p 
0.05. Bars represent mean ± SEM.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONSUPPLEMENTARY DATAFUNDINGREFERENCES |
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Tissue Distribution of Aldhs
Fourteen tissues were analyzed for mRNA of 15 Aldh isozymes. These tissues include liver, kidney, lung, stomach, duodenum, jejunum, ileum, large intestine, heart, brain, gonads (testes and ovaries), placenta, and uterus. mRNA levels for each gene in each tissue are reported as the average ± SEM of five C57BL/6 mice. It should be noted that RLU levels should only be compared for the same gene at different tissues, ages, or induction by MEIs. Therefore, comparison between different genes should not be performed based on RLU readings.
Aldh1a1 mRNA was expressed in all tissues examined except kidney. Highest mRNA expression was detected in ovary followed by lung, testis, and liver. Aldh1a1 mRNA was also expressed at lower levels in stomach, as well as small and large intestine (Fig. 1). Aldh1a2 mRNA was primarily expressed in gonads followed by uterus; it was also detected at low levels in all other tissues except liver (Fig. 1). Aldh1a3 was highly expressed in placenta, followed by small intestine, brain, gonads, and uterus. Aldh1a3 mRNA was expressed at low levels in kidney, lung, stomach, and large intestine, and was not expressed in liver and heart (Fig. 1).
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Aldh1a7 mRNA expression pattern was similar to Aldh1a1, that is Aldh1a7 mRNA was mainly expressed in lung, liver, gonads, and stomach, followed by duodenum, ovary, and placenta (Fig. 2). Aldh1b1 mRNA was primarily expressed in small and large intestine, however, it was present at low levels in all other tissues (Fig. 2). Aldh2 mRNA was ubiquitously expressed in all tissues examined, with higher expression in liver, lung, large intestine, and ovary (Fig. 2).
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Aldh3a1 mRNA expression was highest in stomach followed by lung. It was expressed at much lower levels in gonads, uterus, and placenta (Fig. 3). Aldh3a2 mRNA was expressed at similar levels in all tissues (Fig. 3). Aldh3b1 mRNA expression was highest in lung, followed by ovary and small intestine, and was detected at lower levels in all other tissues (Fig. 3).
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Aldh4a1 mRNA was expressed at high levels in all tissues examined with the highest expression in kidney, liver, ovary, and placenta (Fig. 4). Aldh6a1 was primarily expressed in kidney followed by heart and gonads. Aldh6a1 was also expressed at lower levels in other tissues with minimum levels in small and large intestine (Fig. 4). The highest expression of Aldh7a1 was in kidney followed by liver, brain, ovary, uterus, and placenta. Aldh7a1 mRNA expression was also lowest in small and large intestine (Fig. 4).
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Aldh8a1 was primarily expressed in kidney and liver, followed by placenta, brain, and gonads (Fig. 5). Aldh9a1 mRNA expression was detected in all tissues, but with highest expression in small intestine, kidney, and liver (Fig. 5). Aldh18a1 was highly expressed in ovary, placenta, uterus, and small intestine, followed by brain, stomach, and testes. Liver and kidney, however, exhibited no Ald18a1 mRNA expression (Fig. 5).
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Some Aldh isozymes exhibited gender differences in their mRNA tissue distribution. Most Aldh isozymes were expressed at slightly higher levels in female hearts than in male hearts, namely Aldh1a1, 1b1, 2, 3a1, 4a1, 6a1, 7a1, and 9a1 (Figs. 1–5). In liver, Aldh3a2 (Fig. 3) and Aldh4a1 (Fig. 4) mRNA expression were higher in females, whereas Aldh3b1 (Fig. 3) was higher in males. In kidney, Aldh3b1 (Fig. 3) mRNA expression was also higher in males, whereas Aldh7a1 (Fig. 4) was higher in females.
Ontogeny of Aldhs
Liver was selected to study the developmental changes in the mRNA expression of Aldhs because a number of Aldh isozymes are highly expressed there. mRNA levels were quantified in tissues from five male and five female mice at ages of –2, 0, 5, 10, 15, 22, 30, and 45 days. The developmental changes in the mRNA expression of Aldh 1a2, 1a3, 3a1, 3b1, and 18a1 isozymes, which are minimally expressed in liver, were determined in pooled samples (five animals per sample) to screen for any unique trends. These Aldh isozymes were all expressed at undetectable or very low levels in the liver before birth and throughout their postnatal development (data not shown).
Figure 6 demonstrates the ontogenic expression pattern of Aldhs in mouse livers. Aldh1a1, and 1a7 mRNA expression was low 2 days before birth and gradually increased until 45 days of age without reaching a plateau. Aldh1b1, 6a1, and 7a1 exhibited a similar trend in their ontogenic pattern, where mRNA expression is low at 2 days before birth, but gradually increases reaching a plateau before 45 days of age. Aldh2 mRNA was detected at a relatively high level before birth (one third of that in adults), remained constant until 5 days of age and then gradually increased to reach adult levels at 30 days of age. Aldh3a2 mRNA expression increased immediately after birth to levels close to that in adults. The mRNA remained constant in males, but continued to increase in females causing a gender difference in mRNA expression at 45 days of age. Aldh4a1 ontogenic pattern was also different between male and female mice. In male mice, mRNA expression reached a maximum at day 22 and gradually decreased afterward, whereas in females, mRNA levels reached a maximum at day 15 and remained constant.
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Induction of Aldhs by MEIs
Male C57BL/6 mice were dosed with five groups of prototypical microsomal enzymes inducers. These inducers include AhR ligands: TCDD, PCB126, and BNF; CAR activators: TCPOBOP, DAS, and PB; PXR ligands: PCN, SPR, and DEX; PPAR
ligands: CLOF, CIPRO, and DEHP; and Nrf2 activators: OPZ, EXQ, and BHA. The effect of these inducers on the expression of the Aldh 1a2, 1a3, 3b1, and 18a1 isozymes, which are lowly expressed in liver, was determined in pooled samples (five animals per sample) to examine for induction. None of these Aldh isozymes were induced by any of the studied inducers (data not shown). The induction of Aldh3a1 mRNA was fully investigated despite its low expression in liver because of the large amount of literature addressing its induction by various inducers.
Figure 7 demonstrates the effect of the various MEIs on the hepatic expression of Aldhs. AhR ligands, TCDD, and BNF, moderately induced the mRNA expression of Aldh1a7, Aldh1b1, and Aldh3a1. The AhR ligand PCB126 had no effect on the expression of any of the Aldh isozymes. The three CAR activators, TCPOBOP, DAS, and PB induced the mRNA expression of Aldh1a1 about 100%, and Aldh1a7 by approximately 200%. However, the hepatic expression of Aldh6a1 and Aldh7a1 were suppressed by TCPOBOP, whereas Aldh8a1 expression was suppressed by PB and DAS. Aldh8a1, Aldh1a7, and Aldh1b1 mRNA expression was induced by all three PXR ligands, PCN, SPR, and DEX; Aldh1a1 was induced by PCN and SPR; whereas Aldh4a1 was only induced by SPR. PPAR activators had the most prominent effect on Aldh isozymes mRNA expression. Clofibrate induced the mRNA expression of almost all Aldh isozymes in mice. Aldh1a1, 1a7, 3a2, and 9a1 mRNA expression was induced by all three PPAR activators (CLOF, CIPRO, DEHP). Aldh1b1, 4a1, and 6a1 were induced by the two PPAR activators (CLOF and DEHP), whereas Aldh7a1, and 8a1 were induced by clofibrate only. Nrf2 activators, especially BHA also induced the mRNA expression of many Aldhs. Aldh1a1 and 1a7 mRNA expression was induced by all Nrf2 activators (OPZ, EXQ, and BHA). Aldh1b1 was induced by two Nrf2 activators (EXQ and BHA), whereas, Aldh3a1, 4a1, 7a1, and 8a1 were induced by BHA only.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONSUPPLEMENTARY DATAFUNDINGREFERENCES |
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Tissue Distribution
Aldhs catalyze a major pathway of phase-I biotransformation of numerous endo- and xenobiotics. Understanding the tissue distribution of Aldh isozymes may help determine their impact on the pharmacokinetics as well as the pharmacological and toxicological profiles of numerous substrates. Most studies in the literature concerning the tissue distribution of Aldhs have been limited to a few tissues, and were not quantitative. These previous studies have primarily been performed in rat and human tissues, with limited data available for mice. The mouse is becoming a more common laboratory species because of the availability of transgenic and gene-knockout mice. Therefore, in the present study we evaluated the relative distribution of Aldh isoform mRNA in 14 tissues in mice.
Previous studies in rats demonstrated that Aldh1a1 mRNA is highly expressed in lung, kidney, liver, skeletal muscle, and testis, and to a lesser extent in heart and brain (Kathmann and Lipsky, 1997; Kathmann et al., 2000). In mice, Aldh1a1 mRNA expression was reported in lung, liver, and testis, and to a lesser extent in small intestine (Hsu et al., 1999). Aldh1a1 protein expression in mice was found to be highest in testis, lung, and stomach, followed by small and large intestine, eye, and ovary, but not detected in brain, heart, kidney, and skin (Haselbeck et al., 1999). Aldh1a1 enzymatic activity was also only found in mouse liver, lung, testes, and ovary (Rout and Holmes, 1996). In humans, Aldh1a1 mRNA expression is highest in liver, kidney, skeletal muscle, pancreas, testis, ovary, lung, and small intestine. Heart, placenta, colon, and brain had undetectable levels (Stewart et al., 1996). In this current report, Aldh1a1 mRNA expression was highest in mouse ovary followed by liver, lung, stomach, and testis. Aldh1a1 mRNA was also detected at low levels at all tissues examined except kidney (Fig. 1). There is a marked difference in Aldh1a1 expression between rats and mice, as kidney is the organ with the highest Aldh1a1 expression in rats, whereas in mice Aldh1a1 is not expressed in kidney. This difference may result from documented differences in the 5'-flanking promoter region of Aldh1a1 gene between mice and rats (Kathmann et al., 2000).
In mice, Aldh1a2 mRNA has been reported to only be expressed in testis, uterus, and ovary, and not detected in kidney, stomach, small and large intestine, lung, liver, skeletal muscle, spleen, brain, or heart (Haselbeck et al., 1999; Hsu et al., 2000; Zhao et al., 1996). Aldh1a2 enzyme activity in mice was also mainly detected in uterus and testis (Mather and Holmes, 1984; Rout and Holmes, 1996; Wang et al., 1996; Zhao et al., 1996). In rats, Aldh1a2 mRNA was only detected in testes, but female sex organs were not examined (Wang et al., 1996). In agreement with the previous data, this current report also demonstrates that the highest mRNA expression of Aldh1a2 is in testes, followed by ovary and uterus. Aldh1a2 was also expressed at a low level in all tissues examined except liver (Fig 1).
Aldh1a3 mRNA has been detected in various parts of the eye, and in the nasal epithelium (Dupe et al., 2003; Marlier and Gilbert, 2004) in both rats and mice. Aldh1a3-null mice results in lethal defects in nasal development. Tissue distribution of Aldh1a3 has not been reported in rodents or humans. This manuscript is the first to report detailed tissue distribution of Aldh1a3 in mice. Aldh1a3 mRNA expression was highest in placenta, and was detected in most tissues except liver and heart (Fig. 1).
In rats, Aldh1a7 mRNA expression is high in liver, kidney, and lung, followed by colon, brain, and heart, but was not detected in small intestine (Dunn et al., 1989). However, in another rat study, Aldh1a7 mRNA was very weakly expressed in lung and liver, and was not detected in kidney, testis, heart, brain, spleen, or skeletal muscle (Kathmann et al., 2000). In mice, Aldh1a7 mRNA expression has been reported to be highest in liver and lung, followed by kidney and testis, and was not detected in heart, brain, spleen, or skeletal muscle (Hsu et al., 1999). In this current report, however, Aldh1a7 mRNA expression was not detected in kidney. mRNA expression of Aldh1a7 was highest in lung followed by liver, then testes, and stomach (Fig. 2). Similar to Aldh1a1, Aldh1a7 is expressed at high levels in kidney in rats, whereas not detected in mouse kidney.
In humans, Aldh1b1 mRNA is detected in liver and to a lesser extent in testis, but not in brain (Hsu and Chang, 1991). Another human study also reported the highest mRNA expression in liver, kidney, skeletal muscle, and to a lesser extent in brain, placenta, sex organs, small intestine, and pancreas (Stewart et al., 1996). However in rats, Aldh1b1 mRNA expression was not detected in liver, testis, or eye (the only tissues examined) (Boesch et al., 1996). This current study shows different Aldh1b1 mRNA tissue distribution pattern in mice compared with humans. Aldh1b1 mRNA was primarily expressed in small and large intestine in mice, however, it was present at low levels in other tissues (Fig. 2).
In a previous study in mice, Aldh2 mRNA was detected in liver, followed by kidney, whereas no signal was detected in stomach, brain, spleen, or skeletal muscle (Chang and Yoshida, 1994). However, Aldh2 enzyme activity is widely distributed throughout several mouse tissues, exhibiting highest levels in liver, stomach, pancreas, and adrenal gland, followed by ovary, heart, spleen, and to a lesser extent in testes and urinary bladder (Rout and Holmes, 1996). In humans, Aldh2 activity was detected in 16 tissues, but not in placenta. The same study reported highest activity in liver, lung, kidney, skeletal, and cardiac muscles (Stewart et al., 1996). In the current study, Aldh2 mRNA was also ubiquitously expressed in all tissues examined except placenta. mRNA levels were highest in liver, lung, large intestine, ovary, and kidney (Fig. 2).
Aldh3a1 is known to have undetectable constitutive expression in livers of rats, mice, and humans (Boesch et al., 1996). However, Aldh3a1 expression is upregulated during carcinogenesis, and also highly expressed in many carcinoma cell lines. Aldh3a1 expression is also markedly induced after high doses of TCDD in rats and in many cancer cell lines, therefore, Aldh3a1 is historically known as the TCDD-inducible Aldh. Aldh3a1 is also known as stomach-specific Aldh because of its high expression in stomach. In rats, Aldh3a1 mRNA is highest in stomach, followed by heart and lung, but not detected in small intestine, liver, kidney, colon, testes, brain, adrenal, bladder or skeletal muscle (Dunn et al., 1988). In mice, Aldh3a1 activity was also mainly detected in stomach (Mather and Holmes, 1984; Rout and Holmes, 1996). In humans, Aldh3a1 mRNA has been detected in stomach, but not in liver (Hsu et al., 1992). In this study, Aldh3a1 mRNA expression was also found highest in stomach followed by kidney (Fig. 3).
Aldh3a2 is considered a housekeeping gene because of its wide tissue distribution. In mice, Aldh3a2 mRNA expression was reported to be highest in liver and kidney; followed by stomach, testes, small intestine, and brain; and lowest in heart, skeletal muscle, skin, and thymus (Lin et al., 2000). Ald3a2 mRNA expression is also widely distributed in many human (Chang and Yoshida, 1997) and rat tissues (Demozay et al., 2004), with highest expression found in liver. Data from this current report also demonstrate the expression of Aldh3a2 mRNA in all tissues examined, with highest expression in kidney and ovary, and lowest expression in heart (Fig. 3).
In humans, Aldh3b1 mRNA has its highest abundance in lung followed by kidney and placenta, but not detected in heart, brain, liver, or skeletal muscle (Hsu et al., 1994, 1995). The data in this manuscript, indicate that mouse Aldh3b1 mRNA expression is also highest in lung, followed by ovary and small intestine, and present at detectable levels in all other tissues (Fig. 3).
In humans, Aldh4a1 mRNA expression is highest in liver, kidney, and skeletal muscle; followed by heart, brain, and placenta; and very low in lung and pancreas (Hu et al., 1996). In the current study, we report ubiquitous Aldh4a1 mRNA expression in all tissues examined with highest expression in kidney and liver, followed by ovary and placenta (Fig. 4).
In rats, Aldh6a1 mRNA and protein is highest in kidney, followed by liver and heart, and undetected in brain (Kedishvili et al., 1992). In humans, Aldh6a1 mRNA is expressed at low levels in many tissues and at higher levels in kidney (Hsu et al., 1995). Data from the present study show highest Aldh6a1 mRNA expression in mouse kidney; followed by liver, stomach, heart, and ovary; and lower expression in lung, brain, placenta, and uterus (Fig. 4).
In the human fetus, Aldh7a1 mRNA was highest in kidney, ovary, eye, heart, and cochlea; followed by liver, adrenal, lung, skeletal muscle, and spleen; and no signal in brain (Skvorak et al., 1997). In rats, Aldh7a1 mRNA expression was highest in heart, liver, and kidney, with minimal expression in lung, brain, intestine, pancreas, and brain (Lee et al., 1994). The data in this manuscript indicate that in mice, Aldh7a1 mRNA expression is highest in mice kidney and liver, followed by brain, gonads, placenta, and uterus; and to a lesser extent in all other tissues examined (Fig. 4). Therefore, tissue distribution of Aldh7a1 is conserved between rodents and humans.
Aldh8a1 mRNA has been reported to be expressed in only kidney and liver in mice (Lin et al., 2003) and humans (Lin and Napoli, 2000). In the current study, we report similar results in mice. Aldh8a1 mRNA expression was highest in kidney followed by liver, and lower expression in placenta, gonads, and brain (Fig. 5).
In humans, Aldh9a1 mRNA is highly expressed in kidney, liver, and skeletal muscle, followed by pancreas, heart, placenta, and lung (Lin et al., 1996). In a previous study with human tissues, Aldh9a1 mRNA was also found to be highest in kidney, liver, skeletal muscle, and heart (Hsu et al., 1995). Western blotting showed the highest protein expression in human liver, adrenal gland, and kidney; followed by brain and skeletal muscle; with lowest expression in heart, brain, lung, and placenta (Izaguirre et al., 1997). In rats, highest Aldh9a1-enzyme activity was detected in small intestine (Rebouche and Engel, 1980). Tissue distribution of Aldh9a1 mRNA in mice in this current report is similar to the previous human and rat data. Aldh9a1 mRNA was expressed in all mice tissue examined, with highest expression in kidney, small intestine, and liver (Fig. 5).
In humans, Aldh18a1 mRNA has been detected in heart, testis, spleen, skeletal muscle, ovary, prostate, small intestine, and colon, but not in kidney, liver, lung, brain, or placenta (Aral et al., 1996). However, another study reported highest mRNA expression in human ovary, testis, pancreas, and kidney; followed by colon, small intestine, placenta, and heart; and minimum levels in brain, liver, and skeletal muscle (Hu et al., 1999). In rats, the highest Aldh18a1 enzyme activity was found in small intestine (Wakabayashi et al., 1991). The data in this manuscript indicate that Aldh18a1 mRNA expression is highest in ovary, followed by placenta, uterus, and small intestine, and to a lesser extent in stomach and brain. Liver and kidney, however, exhibited no Ald18a1 mRNA expression (Fig. 5). Therefore, it can be concluded that the highest expression of Aldh18a1 is in small intestine and in female sex organs in both rodents and humans.
Ontogeny
Ontogenic pattern of cytosolic, mitochondrial, and microsomal Aldh enzymatic activity was previously studied in mouse livers. Regardless of their subcellular localization, Aldh activity was very low in fetal liver and could be only detected a few days before birth. Mitochondrial and microsomal Aldh activities increased steadily after birth to reach adult levels by 6 weeks of age. However, cytosolic Aldh activity increased dramatically during the period of 3–6 weeks after birth (Timms and Holmes, 1981). The current data show similar ontogenic pattern of Aldh mRNA compared with the previous enzymatic activity data. The cytosolic Aldh1a1 and 1a7 mRNA levels were very low 2 days before birth, increased after birth and started to increase rapidly 22 days after birth (Fig. 6). However, Aldh3a2 mRNA expression increased immediately after birth to levels close to that in adults. The mRNA remained constant in males, but continued to increase in females causing a gender difference in mRNA expression at 45 days of age (Fig. 6).
In guinea pigs, low Km Aldh activity (mainly Aldh2) gradually increased in fetal livers during gestation, and reached similar adult levels only 2 days after birth. High Km Aldh activity (mainly Aldh1a1) in fetal livers, also gradually increased during gestation, but was only half adult levels 2 days after birth (Card et al., 1989). However, in rats, neonatal low and high Km Aldh activity were only 40% and 4–15% of adult activity, respectively (Sjoblom et al., 1978). The current report in mice demonstrates that Aldh1a1 mRNA levels are less than 10% of adult levels 2 days before birth, and gradually increase until 45 days of age. Aldh2 mRNA levels were about one-third of that in adult mice 2 days before birth and gradually increased until 30 days of age.
It has previously been shown that total Aldh activity is undetectable in rat livers 10 days before birth, and gradually increases until 49 days of age (Lindahl, 1977). The current data in mice also illustrate that the mRNA of various Aldh isozymes are lower in mice fetuses than adult mice, and gradually increase after birth to reach adult levels at 15–45 days of age.
Induction
Induction of phase-I drug-metabolizing enzymes, especially CYPs, and the resulting metabolic activation/deactivation is well characterized. Chemicals that induce the gene expression of Cyps might similarly affect the expression of Aldhs. Therefore, we studied the effect of 15 prototypical microsomal metabolizing enzyme inducers, which are known to induce Cyp enzymes by activating five distinct transcription factors (three inducers in each group), on the hepatic mRNA expression of individual Aldhs in male mice.
The role of AhR in the transcriptional regulation of Aldh3a1 in hepatocarcinogenesis has been studied thoroughly. In normal rat liver, the major Aldh activity prefers aliphatic aldehyde substrates, such as propanyldehyde with NAD+ as the cofactor (P/NAD+ activity). In hepatoma cells, a new activity appears due to the appearance of an Aldh isoenzyme that is not present in normal livers, which prefers aromatic aldehyde substrates, such as benzaldehyde and NADP+ as a cofactor (B/NADP+ activity) (Lindahl and Evces, 1984). This isozyme is also induced in normal rat liver by high doses of TCDD (higher than 100 µg/kg) (Deitrich et al., 1977; Lindahl and Evces, 1984). Furthermore, this isozyme is very similar to the normal dominant Aldh found in lung and stomach, known as stomach-specific Aldh (Yin et al., 1989). This isozyme was later cloned, found to be responsible for the hepatoma cells B/NADP+ activity, identical to the stomach-specific Aldh, and has been referred to as TCDD-inducible or tumor-associated Aldh (Chang et al., 1998; Hsu et al., 1992). This isozyme is currently known as Aldh3a1 (Vasiliou et al., 1999).
AhR was suggested to mediate, at least in part, the TCDD-mediated induction of Aldh3a1 in rats and hepatoma cell lines (Dunn et al., 1988), but not the constitutive tissue-specific expression of Aldh3a1, as shown in AhR-null mice (Korkalainen et al., 1995). Aldh3A1 expression is induced to different extents by TCDD and other AhR ligands in various rat hepatoma cell lines (Huang and Lindahl, 1990; Lin et al., 1984; Takimoto et al., 1991, 1992). In rats, in vivo, Aldh3a1 is relatively refractory to induction by TCDD, as a relatively high dose is required (Deitrich et al., 1977; Germolec et al., 1996; Tank et al., 1986). At least a 10-fold higher dose of TCDD is needed for half maximal induction of Aldh3a1, compared with the typical AhR target gene, Cyp1a1 (Dunn et al., 1988; Germolec et al., 1996; Takimoto et al., 1992). Aldh3a1 expression was induced in mouse hepatoma cell lines (Marks-Hull et al., 1997; Torronen et al., 1992; Vasiliou et al., 1993), however, in vivo, doses up to 100 µg/kg (Marks-Hull et al., 1997) or 200 µg/kg (Vasiliou et al., 1993) of TCDD did not increase Aldh3a1 mRNA expression. In contrast, these high doses of TCDD induce Aldh3a1 in both CULTURED cells and intact rats (Vasiliou et al., 1993, 1996). A similar phenomenon was also observed with another AhR ligand, 3-methylcholanthrene (3MC), where Aldh3a1 activity was markedly induced in rat but not in mice (Vasiliou et al., 1989). In agreement, with previous in vivo studies, this current data show the lack of induction of Aldh3a1 by TCDD in mouse livers (Fig. 7).
AhR ligands, including 3MC, benzo[a]pyrene, and other polyaromatic hydrocarbon compounds, have been reported to minimally induce cytosolic Aldh NAD+-dependent activity (Marselos and Vasiliou, 1991; Marselos et al., 1987; Pappas et al., 2003; Vasiliou and Marselos, 1989a, b; Vasiliou et al., 1989). This might result from Aldh1a7 induction, because the present data illustrate mild induction of cytosolic Aldh1a7 by TCDD in mice. TCDD and 3MC did not induce Aldh3a2 (Vasiliou et al., 1996), Aldh1a1, nor Aldh2 in rats (Boesch et al., 1996). In rats, TCDD treatment results in a small increase in mitochondrial and microsomal Aldh activity, however, this increase was explained by contamination from cytosolic fractions (Tank et al., 1986). In agreement with these reports, in this current study, AhR ligands did not increase the expression of the microsomal (Aldh3a2), or the mitochondrial (Aldh2, 4a1, and 6a1) Aldhs (Fig. 7) in mice.
Cytosolic NAD+-dependent Aldh activity in rats was previously shown to be induced by PB to various degrees, ranging from no induction to 20-fold induction, depending on the rat strain, dose, and dosing regimen (Ganem and Jefcoate, 1998; Jones and Lubet, 1992; Pappas et al., 2001, 2003; Vasiliou and Marselos, 1989a,b; Vasiliou et al., 1989). Induction by PB was also reported in mice, but to a lower magnitude (Timms and Holmes, 1981; Vasiliou et al., 1989). This enzymatic induction was attributed to the upregulation of PB-inducible Aldh isozyme. The identity of PB-inducible Aldh was commonly interchanged between Aldh1a1 and Aldh1a7 (Dunn et al., 1989; Kathmann et al., 2000). PB-inducible Aldh was then cloned and referred to as Aldh1a7 (Dunn et al., 1989; Hsu et al., 1999; Kathmann et al., 2000; Vasiliou et al., 1999). The current data demonstrate the induction of both Aldh1a1 and Aldh1a7 in mouse livers by PB (Fig. 7). Furthermore, other CAR activators (TCPOBOP, DAS) also induced both isozymes to a similar extent.
It was previously reported that mitochondrial and microsomal Aldh (Timms and Holmes, 1981) activities as well as the B/NADP+ are not affected by PB treatment in humans, rats, and mice (Lin et al., 1984; Marselos et al., 1987; Tank et al., 1986; Vasiliou and Marselos, 1989a; Vasiliou et al., 1989). The present data in mice also demonstrate that PB does not affect the mRNA expression of the mitochondrial (Aldh2, 4a1, 6a1, and 9a1), the microsomal (Aldh3a2), and the B/NADP+-specific (Aldh3a1) Aldhs in mice (Fig. 7).
The PPAR ligand (clofibrate) has been previously shown to induce rat Aldh enzyme activity in rat liver microsomal and mitochondrial (except mitochondrial Aldh2) fractions, but not the cytosolic fraction (Antonenkov et al., 1985; Panchenko et al., 1985). Clofibrate did not affect Aldh2 mRNA expression in rats. Furthermore, Aldh2 mRNA expression was not different in PPAR-null mice (Crabb et al., 2001). In mice, clofibrate was shown to induce Aldh3a2 and failed to affect Aldh3a1 mRNA expression (Vasiliou et al., 1996). DEHP (another PPAR ligand) was also shown to induce Aldh3a2 mRNA expression in mice (Wong and Gill, 2002). In agreement with the previous reports, the current results demonstrate induction of the microsomal (Aldh3a2), and the mitochondrial (4a1, 6a1, and 9a1) Aldhs, and there was no induction of Aldh2 and Aldh3a1 by CLOF nor by other PPAR ligands in mice (Fig. 7).
The effect of DEX (a PXR ligand) on the expression of Aldhs was examined previously. DEX did not affect Aldh2 and Aldh3a1 mRNA expression in rat and human cell cultures (Crabb et al., 1995; Falkner et al., 1999; Prough et al., 1997). Aldh1a3 expression was also not upregulated by transfecting carcinoma cell lines with RXR, VDR, GR, or PPAR constructs (Grun et al., 2000). The current data also demonstrate the lack of induction of Aldh1a3 (data not shown), Aldh2, and Aldh3a1 by any of the PXR ligands in livers of mice. In contrast, Aldh1a1, Aldh1a7, and Aldh1b1 mRNA expression was induced by all three PXR ligands (PCN, SPR, and DEX) in mice livers (Fig. 7).
The role of Nrf2 in the transcriptional regulation of Aldhs has not been previously studied in any species. Nrf2 activators, especially BHA, increased the mRNA expression of many Aldhs. Aldh1a1 and 1a7 mRNA expression was induced by all Nrf2 activators (OPZ, EXQ, and BHA). Aldh1b1 was induced by 2 Nrf2 activators (EXQ and BHA), whereas, Aldh3a1, Aldh4a1, Aldh7a1, and Aldh8a1 (Fig. 12) were induced by BHA only.
In summary, the present data demonstrate the relative tissue distribution of 15 Aldh isozymes mRNA in 14 tissues of mice, hepatic ontogenic pattern, and induction of the most abundant isozymes in mice livers. 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. mRNA expression of Aldh isozymes was lower in pups than in adults in mice, and gradually increased after birth to reach adult levels between 15 and 45 days of age. AhR ligands induced the liver mRNA expression of Aldh1a7, 1b1, and 3a1. CAR activators induced the liver mRNA expression of Aldh1a1 and 1a7. PXR ligands and Nrf2 activators induced the liver mRNA expression of Aldh1a1, 1a7, and 1b1. PPAR ligands, specially CLOF, induced the mRNA expression of almost all Aldhs.
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONSUPPLEMENTARY DATAFUNDINGREFERENCES |
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Supplementary data are available online at http://toxsci.oxfordjournals.org/.
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONSUPPLEMENTARY DATAFUNDINGREFERENCES |
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National Institute of Health grants (ES-09649, ES-09716); and COBRE grant (P20-RR-021940).
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The authors would like to thank David Buckley, Xiaohong Lei, and Drs Chuan Chen and Hong Lu for technical assistance.
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