Dataset Information

Effect of prototypical inducers on ligand activated nuclear receptor regulated drug disposition genes in rodent hepatic and intestinal cells.

ABSTRACT:

Aim

The aim of this study was to investigate the impact on expression of mRNA and protein by paradigm inducers/activators of nuclear receptors and their target genes in rat hepatic and intestinal cells. Furthermore, assess marked inter laboratory conflicting reports regarding species and tissue differences in expression to gain further insight and rationalise previously observed species differences between rodent and human based systems.

Methods

Quantitative real time-polymerase chain reaction (QRT-PCR) and immunoblots were used to assess messenger RNA (mRNA) and protein expression for CYP2B2, CYP3A1, CYP3A2, CYP3A9, ABCB1a, ABCB1b, ABCC1, ABCC2, pregnane X receptor (PXR), farnesoid X receptor (FXR) and constituitive androstane receptor (CAR) in rat hepatoma cell line H411E, intestinal cells, Iec-6, and rat primary hepatocytes, in response to exposure for 18 h with prototypical inducers.

Results

Dexamethasone (DEX) and pregnenolone 16alpha carbonitrile (PCN) significantly induced PXR, CYP3A9, ABCB1a and ABCB1b. However, when co-incubated, DEX appeared to restrict PCN-dependent induction. Chenodeoxycholic acid (CDCA) was the only ligand to induce FXR in all three cell types. Despite previously reported species differences between PCN and rifampicin (RIF), both compounds exhibited a similar profile of induction.

Conclusion

Data presented herein may explain some of the discrepancies previously reported with respect to species differences from different laboratories and have important implications for study design.

SUBMITTER: Martin P

PROVIDER: S-EPMC4002700 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

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Publications

Effect of prototypical inducers on ligand activated nuclear receptor regulated drug disposition genes in rodent hepatic and intestinal cells.

Martin Philip P Riley Robert R Thompson Paul P Williams Dominic D Back David D Owen Andrew A

Acta pharmacologica Sinica 20100101 1

<h4>Aim</h4>The aim of this study was to investigate the impact on expression of mRNA and protein by paradigm inducers/activators of nuclear receptors and their target genes in rat hepatic and intestinal cells. Furthermore, assess marked inter laboratory conflicting reports regarding species and tissue differences in expression to gain further insight and rationalise previously observed species differences between rodent and human based systems.<h4>Methods</h4>Quantitative real time-polymerase c ...[more]

PMID: 20048746

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Project description:Niclosamide, an antiparasitic, has been repositioned as a potential therapeutic drug for systemic diseases based on its antiviral, anticancer, and anti-infection properties. However, low bioavailability limits its in vivo efficacy. Our aim was to determine whether metabolic disposition by microsomal P450 enzymes in liver and intestine influences niclosamide's bioavailability in vivo, by comparing niclosamide metabolism in wild-type, liver-Cpr-null (LCN), and intestinal epithelium-Cpr-null (IECN) mice. In vitro stability of niclosamide in microsomal incubations was greater in the intestine than in liver in the presence of NADPH, but it was much greater in liver than in intestine in the presence of UDPGA. NADPH-dependent niclosamide metabolism and hydroxy-niclosamide formation were inhibited in hepatic microsomes of LCN mice, but not IECN mice, compared with wild-type mice. In intestinal microsomal reactions, hydroxy-niclosamide formation was not detected, but rates of niclosamide-glucuronide formation were ∼10-fold greater than in liver, in wild-type, LCN, and IECN mice. Apparent Km and V max values for microsomal niclosamide-glucuronide formation showed large differences between the two tissues, with the intestine having higher Km (0.47 μM) and higher V max (15.8) than the liver (0.09 μM and 0.75, respectively). In vivo studies in LCN mice confirmed the essential role of hepatic P450 in hydroxy-niclosamide formation; however, pharmacokinetic profiles of oral niclosamide were only minimally changed in LCN mice, compared with wild-type mice, and the changes seem to reflect the compensatory increase in hepatic UDP-glucuronosyltransferase activity. SIGNIFICANCE STATEMENT: These results suggest that efforts to increase the bioavailability of niclosamide by blocking its metabolism by P450 enzymes will unlikely be fruitful. In contrast, inhibition of niclosamide glucuronidation in both liver and intestine may prove effective for increasing niclosamide's bioavailability, thereby making it practical to repurpose this drug for treating systemic diseases.

Dataset Information

Effect of prototypical inducers on ligand activated nuclear receptor regulated drug disposition genes in rodent hepatic and intestinal cells.

Aim

Methods

Results

Conclusion

Publications

Effect of prototypical inducers on ligand activated nuclear receptor regulated drug disposition genes in rodent hepatic and intestinal cells.

Similar Datasets

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