Transcription Factor-Mediated Regulation of Carboxylesterase Enzymes in Livers of Mice

Abstract

ABSTRACT:The induction of drug-metabolizing enzymes by chemicals is one of the major reasons for drug-drug interactions. In the present study, the regulation of mRNA expression of one arylacetamide deacetylase (Aadac) and 11 carboxylesterases (Cess) by 15 microsomal enzyme inducers (MEIs) was examined in livers of male C57BL/6 mice. The data demonstrated that Aadac mRNA expression was suppressed by three aryl hydrocarbon receptor (AhR) ligands, two constitutive androstane receptor (CAR) activators, two pregnane X receptor (PXR) ligands, and one nuclear factor erythroid 2-related factor 2 (Nrf2) activator. Ces1 subfamily mRNA expression was not altered by most of the MEIs, whereas Ces2 subfamily mRNA was readily induced by the activators of CAR, PXR, and Nrf2 but not by peroxisome proliferator-activated receptor ␣ activators.Studies using null mice demonstrated that 1) AhR was required for the 2,3,7,8-tetrachlorodibenzo-p-dioxin-mediated suppression of Aadac and Ces3a; 2) CAR was involved in the 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene-mediated induction of Aadac, Ces2c, Ces2a, and Ces3a; 3) PXR was required for the pregnenolone-16␣-carbonitrile-mediated induction of Aadac, Ces2c, and Ces2a; 4) Nrf2 was required for the oltipraz-mediated induction of Ces1g and Ces2c; and 5) PXR was not required for the DEX-mediated suppression of Cess in livers of mice. In conclusion, the present study systematically investigated the regulation of Cess by MEIs in livers of mice and demonstrated that MEIs modulated mRNA expression of mouse hepatic Cess through the activation of AhR, CAR, PXR, and/or Nrf2 transcriptional pathways.

Carboxylesterases Are Uniquely Expressed among Tissues and Regulated by Nuclear Hormone Receptors in the Mouse

“…In particular, treating rodents with the PPARa ligands clofibrate and WY14,643, or perfluorinated fatty acids resulted in increased CES enzyme activity of five to six subclasses defined by substrate specificity. Most recently, two reports have demonstrated that fibrate treatment of C57/Bl6 mice for 5 days to 2 weeks does not upregulate hepatic Ces1d mRNA levels (Dolinsky et al, 2003;Zhang et al, 2012). These recent findings differ from our results showing that administration of the potent, specific PPARa agonist GW7647 to A129/SvJ mice is associated with increased expression of Ces1d, Ces1e, Ces1f, Ces2c and Ces2e mRNA in liver.…”

“…The utility of our qPCR method is readily apparent by the distinct expression patterns of Ces mRNAs, thus confirming the specificity of primers. In addition, the rank order of Ces mRNA levels in liver tissue observed in our studies is consistent with recently published findings for 11 Ces members using a branched-DNA signal amplification assay (Zhang et al, 2012). Hence, our qPCR method provides a reliable means to determine steady-state levels of Ces mRNA in the mouse.…”

“…The role of carboxylesterases in drug metabolism has been widely appreciated, and previous work from the Klasseen and Staudinger groups has convincingly shown that the xenobiotic nuclear hormone receptors PXR and CAR increase expression of Ces2a (previously Ces6) and Ces2c (Xu et al, 2009;Staudinger et al, 2010;Zhang et al, 2012). Our work confirms these findings (Fig.…”

“…Numerous reports have appeared describing the distribution, regulation and function of various carboxylesterases in the mouse model (Poole et al, 2001;Holmes et al, 2009Holmes et al, , 2010aXu et al, 2009;Staudinger et al, 2010;Zhang et al, 2012). However, with the confusion regarding Carboxylesterase mRNA Distribution and Regulation in Mice nomenclature and ortholog assignment, and the nonselectivity of some oligonucleotide and antibody probes, the reliability of these findings has been uncertain.…”

P-Glycoprotein, CYP3A, and Plasma Carboxylesterase Determine Brain and Blood Disposition of the mTOR Inhibitor Everolimus (Afinitor) in Mice

“…As Ces1b is hardly expressed in mouse liver (28,29), the substantially expressed carboxylesterase Ces1c is the most likely candidate everolimus-binding protein in plasma. A range of other esterases, including Ces2e, Ces3a, Aadac, and Pon1, 2, and 3, were not upregulated in Abcb1a/ 1b À/À mice (27), and thus unlikely to be involved in everolimus protection in the knockout strains studied here.…”