Activation of Steroid and Xenobiotic Receptor (SXR, NR1I2) and Its Orthologs in Laboratory, Toxicologic, and Genome Model Species

Milnes, Matthew R.; Garcia, Adriana; Grossman, Emily D.; Grün, Felix; Shiotsugu, Jason; Tabb, Michelle M.; Kawashima, Yukio; Katsu, Yoshinao; Watanabe, Hidenobu; Iguchi, Taisen; Blumberg, Bruce

doi:10.1289/ehp.10853

Cited by 50 publications

(64 citation statements)

References 33 publications

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“…As noted with other inducers, we observed a significant time delay between rifampicin administration and the onset of induction, with the peak response occurring approximately 48 h after the first dose of rifampicin (Gordi et al, 2005;Magnusson et al, 2006). This delayed onset is related to the complex series of events that must occur to trigger an increase in transcription (Moore et al, 2002;Milnes et al, 2008). We accounted for this temporal delay by using a series of transduction compartments, which introduces time lags between the rifampicin liver concentration and the increase in mRNA levels.…”

Section: Discussionmentioning

confidence: 67%

Pharmacokinetic-Pharmacodynamic Modeling of Rifampicin-Mediated Cyp3a11 Induction in Steroid and Xenobiotic X Receptor Humanized Mice

Raybon

Pray²,

Morgan³

et al. 2010

J Pharmacol Exp Ther

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The purpose of this study was to develop a mechanistic pharmacokinetic-pharmacodynamic (PK-PD) model to describe the effects of rifampicin on hepatic Cyp3a11 RNA, enzymatic activity, and triazolam pharmacokinetics. Rifampicin was administered to steroid and xenobiotic X receptor (SXR) humanized mice at 10 mg/kg p.o. (every day for 3 days) followed by triazolam (4 mg/kg p.o.) 24 h after the last dose of rifampicin. Rifampicin and triazolam concentrations and Cyp3a11 RNA expression and activity in the liver were measured over the 4-day period. Elevations in Cyp3a11 RNA expression were observed 24 h after the first dose of rifampicin, reaching a maximum (ϳ10 times baseline) after the third dose and were sustained until day 4 and began declining 48 h after the last rifampicin dose. Similar changes in enzymatic activity were also observed. The triazolam serum area under the curve (AUC) was 5-fold lower in mice pretreated with rifampicin, consistent with enzyme induction. The final PK-PD model incorporated rifampicin liver concentration as the driving force for the time-delayed Cyp3a11 induction governed by in vitro potency estimates, which in turn regulated the turnover of enzyme activity. The PK-PD model was able to recapitulate the delayed induction of Cyp3a11 mRNA and enzymatic activity by rifampicin. Furthermore, the model was able to accurately anticipate the reduction in the triazolam plasma AUC by integrating a ratio of the predicted induced enzyme activity and basal activity into the equations describing triazolam pharmacokinetics. In conjunction with the SXR humanized mouse model, this mathematical approach may serve as a tool for predicting clinically relevant drug-drug interactions via pregnane X receptor-mediated enzyme induction and possibly extended to other induction pathways (e.g., constitutive androstane receptor).

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Section: Discussionmentioning

confidence: 67%

Pharmacokinetic-Pharmacodynamic Modeling of Rifampicin-Mediated Cyp3a11 Induction in Steroid and Xenobiotic X Receptor Humanized Mice

Raybon

Pray²,

Morgan³

et al. 2010

J Pharmacol Exp Ther

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“…The consensus cynoPXR sequence showed two amino acid residue differences at Cys182 and Glu189 in the LBD when it was compared with the previously published partial cynoPXR sequence (GenBank accession number EU153253), which has Tyr and Arg at the same positions, respectively (Milnes et al, 2008). It also showed two wobble base pair changes relative to the rhesus PXR sequence at nucleotide positions 354 and 1158 of the open reading frame (data not shown).…”

Section: Molecular Cloning and Sequencing Of Cynopxrmentioning

confidence: 80%

Evaluation of Cynomolgus Monkey Pregnane X Receptor, Primary Hepatocyte, and in Vivo Pharmacokinetic Changes in Predicting Human CYP3A4 Induction

Kim¹,

Dinchuk²,

Anthony³

et al. 2009

Drug Metab Dispos

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ABSTRACT:Monkeys have been proposed as an animal model to predict the magnitude of human clinical drug-drug interactions caused by CYP3A4 enzyme induction. To evaluate whether the cynomolgus monkey can be an effective in vivo model, human CYP3A4 inducers were evaluated both in vitro and in vivo. First, a full-length pregnane X receptor (PXR) was cloned from the cynomolgus monkey, and the sequence was compared with those of rhesus monkey and human PXR. Cynomolgus and rhesus monkey PXR differed by only one amino acid (A68V), and both were highly homologous to human PXR (ϳ96%). When the transactivation profiles of 30 compounds, including known inducers of CYP3A4, were compared between cynomolgus and human PXR, a high degree of correlation with EC 50 values was observed. These results suggest that cynomolgus and human PXR respond in a similar fashion to these ligands. Second, two known human CYP3A4 inducers, rifampicin and hyperforin, were tested in monkey and human primary hepatocytes for induction of CYP3A enzymes. Both monkey and human hepatocytes responded similarly to the inducers and resulted in increased RNA and enzyme activity changes of CYP3A8 and CYP3A4, respectively. Lastly, in vivo induction of CYP3A8 by rifampicin and hyperforin was shown by significant reductions of midazolam exposure that were comparable with those in humans. These results show that the cynomolgus monkey can be a predictive in vivo animal model of PXR-mediated induction of human CYP3A4 and can provide a useful assessment of the resulting pharmacokinetic changes of affected drugs.

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“…Sodium luciferin solution (100 l; 1ϫ luciferase base buffer, 0.5 mM ATP, 5 mM DTT, 0.15 mg/ml coenzyme A, 0.5 mM sodium luciferin) and 20 l of cleared lysate were added to a 96-well plate in triplicate. Relative light units were measured using an ML3000 luminometer, then normalized to total protein (Milnes et al, 2008). Error bars represent biological replicates (multiple pools of five embryos derived from the same female frog).…”

Section: Luciferase Assaymentioning

confidence: 99%

“…Development 139 (6) Relative light units were normalized to total protein (Milnes et al, 2008). Error bars represent biological replicates (multiple pools of five embryos derived from the same female frog).…”

Section: Research Articlementioning

confidence: 99%

RIPPLY3 is a retinoic acid-inducible repressor required for setting the borders of the pre-placodal ectoderm

et al. 2012

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SUMMARYRetinoic acid signaling is a major component of the neural posteriorizing process in vertebrate development. Here, we identify a new role for the retinoic acid receptor (RAR) in the anterior of the embryo, where RAR regulates Fgf8 expression and formation of the pre-placodal ectoderm (PPE). RAR2 signaling induces key pre-placodal genes and establishes the posterolateral borders of the PPE. RAR signaling upregulates two important genes, Tbx1 and Ripply3, during early PPE development. In the absence of RIPPLY3, TBX1 is required for the expression of Fgf8 and hence, PPE formation. In the presence of RIPPLY3, TBX1 acts as a transcriptional repressor, and functions to restrict the positional expression of Fgf8, a key regulator of PPE gene expression. These results establish a novel role for RAR as a regulator of spatial patterning of the PPE through Tbx1 and RIPPLY3. Moreover, we demonstrate that Ripply3, acting downstream of RAR signaling, is a key player in establishing boundaries in the PPE. represses the ability of TBX1 to activate reporter gene constructs in vivo and this inhibition depends on the association of RIPPLY3 with its co-repressor GROUCHO and with TBX1. In agreement with our predictions, RIPPLY3 knockdown perturbs the borders of PPE marker expression. These results demonstrate a novel role for RAR in the precise positioning of the PPE boundaries and establish RIPPLY3 as a key factor that demarcates the boundaries of the PPE. MATERIALS AND METHODS Ripply3 alignment and construction of a phylogenetic treeRipply sequences were obtained from Genbank and Uniprot databases (Benson et al., 2008;Uniprot Consortium, 2009), aligned with MAFFT (L-INS-i algorithm) (Katoh et al., 2009;Katoh et al., 2005) and a phylogenetic tree constructed with PROml, version 3.69 (Protein Maximum Likelihood) (Felsenstein, 2005). Default settings were used, global rearrangements (-G) were performed, and the outgroup (-O) was set to amphioxus. The resultant tree was drawn with FigTree (Rambaut, 2007). Conserved domains of the Ripply gene family were visualized with WebLogo (Crooks et al., 2004;Schneider and Stephens, 1990). EmbryosXenopus eggs were fertilized in vitro as described previously (Blumberg et al., 1997;Koide et al., 2001) and embryos staged according to Nieuwkoop and Faber (Nieuwkoop and Faber, 1967). Embryos were maintained in 0.1ϫ MBS until appropriate stages or treated with 1 M agonist (TTNPB) and 1 M antagonist (AGN193109) as described (Arima et al., 2005). MicroinjectionEmbryos were injected bilaterally or unilaterally at the two-cell stage with combinations of gene specific morpholinos (MO), mRNAs and 100 pg/embryo -galactosidase mRNA lineage tracer. MOs used for this study are found in supplementary material Table S1. Control embryos were injected with 20 ng standard control MO: CCT CTT ACC TCA GTT ACA ATT TAT A (GeneTools). The following plasmids were constructed by PCR amplification of the protein-coding regions of the indicated genes and cloning into the expression vector pCDG1: xRARa2.2 (Sharpe, ...

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Activation of Steroid and Xenobiotic Receptor (SXR, NR1I2) and Its Orthologs in Laboratory, Toxicologic, and Genome Model Species

Cited by 50 publications

References 33 publications

Pharmacokinetic-Pharmacodynamic Modeling of Rifampicin-Mediated Cyp3a11 Induction in Steroid and Xenobiotic X Receptor Humanized Mice

Pharmacokinetic-Pharmacodynamic Modeling of Rifampicin-Mediated Cyp3a11 Induction in Steroid and Xenobiotic X Receptor Humanized Mice

Evaluation of Cynomolgus Monkey Pregnane X Receptor, Primary Hepatocyte, and in Vivo Pharmacokinetic Changes in Predicting Human CYP3A4 Induction

RIPPLY3 is a retinoic acid-inducible repressor required for setting the borders of the pre-placodal ectoderm

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