Expression and induction by rifampicin of CAR- and PXR-regulated CYP2B and CYP3A in liver, kidney and airways of pig

Nannelli, Annalisa; Chirulli, V.; Longo, Vincenzo; Gervasi, Pier Giovanni

doi:10.1016/j.tox.2008.08.004

Cited by 55 publications

(42 citation statements)

References 46 publications

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“…However, RIF only induced the expression of CYP3A46 for four times in the porcine liver (Nannelli et al, 2008). Our studies drew similar results that the expression of CYP3A46 at the mRNA level was induced by RIF only up to five fold.…”

Section: Transcriptional Regulation Of the Porcine Cyp3a46 Genesupporting

confidence: 84%

“…Their expression patterns and inducible aspects are different, indicating the underlying of different regulatory mechanisms (Nannelli et al, 2008;Yao et al, 2012;Shang et al, 2013). However, related research is limited.…”

Section: Transcriptional Regulation Of the Porcine Cyp3a46 Genementioning

confidence: 99%

“…Both studies evidence CYP3A46 as a key enzyme in the metabolism of xenobiotics. CYP3A46 is mainly expressed in the liver, and its expression can be induced by RIF (Nannelli et al, 2008). Nevertheless, the regulatory mechanism is yet to be clarified for the expression of CYP3A46 in comparison with the well-studied human CYP3A4 in the basal and drug-mediated regulations.…”

Section: Introductionmentioning

confidence: 99%

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Role of Specificity Protein 1, Hepatocyte Nuclear Factor 1α, and Pregnane X Receptor in the Basal and Rifampicin-Induced Transcriptional Regulation of Porcine Cytochrome P450 3A46

et al. 2015

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Cytochrome P450 (CYP) 3A46, one of human CYP3A4 homologs, functions as a key enzyme in the metabolism of xenobiotics in pigs. However, the regulatory mechanism for the transcriptional activation of CYP3A46 in porcine liver remains unknown. In this study, we confirmed that CYP3A46 is constitutively expressed in porcine primary hepatocytes, and its expression was significantly induced by rifampicin (RIF) instead of dexamethasone. We further found that a proximal GC box and a distal hepatocyte nuclear factor 1 (HNF1) binding site within the 59-flanking region of CYP3A46 are the important cis-regulatory elements involved in regulating the constitutive expression of CYP3A46, via recruiting specificity protein 1 (Sp1) and HNF1a, respectively. Furthermore, we revealed that HNF1a and pregnane X receptor (PXR) activate the RIF-mediated transcription of CYP3A46 by binding to the distal HNF1 binding site and the proximal direct repeats of AGGTCA separated by 4 bases motif, respectively. Meanwhile, HNF1a is also involved in regulating RIF-induced expression of CYP3A4 through a novel distal HNF1 binding site identified in the xenobiotic-responsive enhancer module. In summary, our data demonstrate that several transcription factors, including Sp1, HNF1a, and PXR, function in the basal and RIF-mediated transcriptional regulation of CYP3A46 by binding to their related cis-regulatory elements in the proximal promoter and distal enhancer.

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Section: Transcriptional Regulation Of the Porcine Cyp3a46 Genesupporting

confidence: 84%

Section: Transcriptional Regulation Of the Porcine Cyp3a46 Genementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Role of Specificity Protein 1, Hepatocyte Nuclear Factor 1α, and Pregnane X Receptor in the Basal and Rifampicin-Induced Transcriptional Regulation of Porcine Cytochrome P450 3A46

et al. 2015

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“…Inhibition of BQOD BQOD is another reaction used as a marker of CYP3A in various species including pig (Nannelli et al, 2008), rat, rabbit (Chirulli et al, 2005) and fish (Smith and Wilson, 2010). In this study, KTZ was shown to be a competitive inhibitor of BQOD activity in salmon (Figure 4).…”

Section: Inhibition Patternmentioning

confidence: 64%

“…Inhibition of BFCOD BFCOD activity is used as a marker of CYP3A in humans (Renwick et al, 2000;Appiah-Opong et al, 2007) and pigs (Nannelli et al, 2008), although some studies have used BFC as a marker of CYP1A/2B in humans and rats (Price et al, 2008). In fish, BFC is believed to be the specific substrate for CYP3A (Christen et al, 2009).…”

Section: Inhibition Patternmentioning

confidence: 99%

Comparison of three fluorescent CYP3A substrates in two vertebrate models: pig and Atlantic salmon

Žlábek¹,

Zamaratskaia²

2012

Animal

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We investigated in vitro inhibitory effects of ketoconazole (KTZ) on cytochrome P450 activity in microsomes from pigs and Atlantic salmon. The following enzymatic reactions were studied: 7-benzyloxyresorufin and 7-ethoxyresorufin O-dealkylation (BROD and EROD, respectively), 7-benzyloxy-4-trifluoromethylcoumarin O-debenzylation (BFCOD) and 7-benzyloxyquinoline O-debenzylation (BQOD). KTZ was a potent non-competitive inhibitor of BROD and BQOD in the microsomes from pigs, whereas in the microsomes from Atlantic salmon, these reactions were competitively inhibited by KTZ. BFCOD activity was inhibited by KTZ in a non-competitive manner in both species. KTZ non-competitively inhibited EROD in Atlantic salmon, but not in porcine microsomes. The activity of BROD and BQOD was higher in male than that in female pigs, but the activity of BFCOD showed no sex-related differences.

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Induction of Cytochrome P450 Systems

Coleman

2010

Human Drug Metabolism

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Expression and induction by rifampicin of CAR- and PXR-regulated CYP2B and CYP3A in liver, kidney and airways of pig

Cited by 55 publications

References 46 publications

Role of Specificity Protein 1, Hepatocyte Nuclear Factor 1α, and Pregnane X Receptor in the Basal and Rifampicin-Induced Transcriptional Regulation of Porcine Cytochrome P450 3A46

Role of Specificity Protein 1, Hepatocyte Nuclear Factor 1α, and Pregnane X Receptor in the Basal and Rifampicin-Induced Transcriptional Regulation of Porcine Cytochrome P450 3A46

Comparison of three fluorescent CYP3A substrates in two vertebrate models: pig and Atlantic salmon

Induction of Cytochrome P450 Systems

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