Tissue Distribution, Ontogeny, and Chemical Induction of Aldo-Keto Reductases in Mice

Abstract

Aldo-keto reductases (Akrs) are a conserved group of NADPHdependent oxido-reductase enzymes. This study provides a comprehensive examination of the tissue distribution of the 16 substrate-metabolizing Akrs in mice, their expression during development, and whether they are altered by chemicals that activate distinct transcriptional factor pathways. Akr1c6, 1c14, 1c20, and 1c22 are primarily present in liver; Akr1a4, 1c18, 1c21, and 7a5 in kidney; Akr1d1 in liver and kidney; Akr1b7 in small intestine; Akr1b3 and Akr1e1 in brain; Akr1b8 in testes; Akr1c14 in ovaries; and Akrs1c12, 1c13, and 1c19 are expressed in numerous tissues. Liver expression of Akr1d1 and Akr1c is lowest during prenatal and postnatal development. However, by 20 days of age, liver Akr1d1 increases 120-fold, and Akr1c mRNAs increase as much as 5-fold (Akr1c19) to 1000-fold (Akr1c6). Treatment of mice with chemical activators of transcription factors constitutive androgen receptor (CAR), pregnane X receptor (PXR), and the nuclear factor-erythroid-2 (Nrf2) transcription factor alters liver mRNAs of Akrs. Specifically, CAR activation by 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) increases mRNAs of Akr1b7, Akr1c6, Akr1c19, and Akr1d1, whereas PXR activation by 5-pregnenolone-16a-carbonitrile (PCN) increases the mRNA of Akr1b7 and suppresses mRNAs of Akr1c13 and Akr1c20. The Nrf2 activator 2-cyano-3,12-dioxooleana-1,9-dien-28-imidazolide (CDDO-Im) induces mRNAs of Akr1c6 and Akr1c19. Moreover, Nrf2-null and Nrf2 overexpressing mice demonstrate that this induction is Nrf2-dependent.

RNA Sequencing Quantification of Xenobiotic-Processing Genes in Various Sections of the Intestine in Comparison to the Liver of Male Mice

“…For Pons, the present study has shown that both Pon2 and 3 mRNAs are lower in the jejunum and ileum than in the large intestine, in contrast to the previous report of similar levels (Cheng and Klaassen, 2012). For Akrs, the mRNAs of Akr1a1/1a4, 1b3, 1c12, 1c13, 1c19, and 1e1 in certain tissue(s) in the present study are not fully consistent with a previous report (Pratt-Hyatt et al, 2013). For P450s, there are some inconsistencies between the present study and a previous report (Renaud et al, 2011) on Cyp2b13, 2d12, 2j9, 4f14, 4f37, and 4v3.…”

“…Previously, we and others have characterized the expression profiles of many XPGs in the liver and intestine of rodents, including carboxylesterases (Cess) (Jones et al, 2013), aldo-keto reductases (Akrs) (Pratt-Hyatt et al, 2013), cytochrome P450s (P450s) (Renaud et al, 2011), alcohol dehydrogenases (Adhs) (Alnouti and Klaassen, 2008), flavin monooxygenases (Fmos) (Janmohamed et al, 2004), UDP-glucuronosyltransferases (Ugts) (Shelby et al, 2003;Buckley and Klaassen, 2007), sulfotransferases (Sults) (Dunn and Klaassen, 1998;, glutathione-S-transferases (Gsts) (Knight et al, 2007), methyltransferases, N-acetyltransferases (Nats), and enzymes for the synthesis of phase II cosubstrates , as well as various Slc transporters Slitt et al, 2002;Lu et al, 2004;Ballatori et al, 2005;Cheng et al, 2005;Lu and Klaassen, 2006;Lickteig et al, 2008) and Abc transporters (Brady et al, 2002;Cherrington et al, 2002;Yu et al, 2002;Chen and Klaassen, 2004;Maher et al, 2005Maher et al, , 2006Tanaka et al, 2005;Cheng and Klaassen, 2009;Cui et al, 2009). Together, these studies have markedly improved our understanding of the tissue-divergent expression patterns of these XPGs.…”

RNA-Seq reveals common and unique PXR- and CAR-target gene signatures in the mouse liver transcriptome

“…The regulation of many hepatic DPGs by PXR and CAR ligands has been characterized in mice using branched DNA amplification (bDNA) assays (Cheng et al, 2005; Maher et al, 2005; Alnouti and Klaassen, 2008a; Alnouti and Klaassen, 2008b; Knight et al, 2008; Buckley and Klaassen, 2009; Cui et al, 2009; Aleksunes and Klaassen, 2012; Cheng and Klaassen, 2012; Zhang et al, 2012; Pratt-Hyatt et al, 2013). The present study using RNA-Seq is consistent with these previous studies regarding the up-regulation of Cyp1a2, Cyp2b10, Aldh1a7, Gsta1, Gsta4, Gstm1-3, Gstt1, Sult1e1, Papss2, Ugt2b34-36, and Mrp2-4, most notably by the chemical activation of CAR by TCPOBOP but also by PCN to a lesser extent; whereas PCN also up-regulates Gstm1-3 and Mrp3 in both studies to a much lesser extent than does TCPOBOP (Figure 3, 8, 11, 12, and 13) (Maher et al, 2005; Alnouti and Klaassen, 2008a; Knight et al, 2008; Buckley and Klaassen, 2009).…”

RNA-Sequencing Quantification of Hepatic Ontogeny of Phase-I Enzymes in Mice

“…The advantages of these models include rapid growth, easy maintenance, and the development of genetic manipulation techniques for mechanistic studies with gainof-function and loss-of-function strategies. Several laboratories, including ours, have examined the ontogenic gene expression profiles in mouse or rat livers for some phase-I genes, including P450s (Hart et al, 2009;Cui et al, 2012b), Ces (Zhu et al, 2009), aldo-keto reductase (Akr) (Pratt-Hyatt et al, 2013), Adh and aldehyde dehydrogenase (Aldh) (Smolen et al, 1990;Alnouti and Klaassen, 2008), Pon (Li et al, 1997), and Fmo (Falls et al, 1995;Cherrington et al, 1998;Janmohamed et al, 2004). The developmental expression patterns of some phase-I genes in mice and rats are similar to those in humans.…”