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Expression and distribution of CYP3A genes, CYP2B22, and MDR1, MRP1, MRP2, LRP efflux transporters in brain of control and rifampicin-treated pigs

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Abstract

The in vivo effect of rifampicin, a potent ligand of PXR, on gene expression of CYP2B22, 3A22, 3A29, 3A46, CAR, PXR and MDR1, MRP1, MRP2, LRP transporters in liver and cortex, cerebellum, midbrain, hippocampus, meninges and brain capillaries of pig was investigated. Animals were treated i.p. with four daily doses of rifampicin (40 mg/kg). The basal mRNA expressions of the individual CYP3As, CYP2B22, CAR, and PXR in various brain regions, except meninges, were about or below 10% of the corresponding hepatic mRNA values, whereas the mRNAs of brain transporters were closer or comparable to those in liver. After pig treatment with rifampicin, the mRNA expression of CYPs and transporters from brain regions did not appear to change, except CYP3A22 and 3A29 in cortex and hippocampus, CYP2B22 in meninges. An enzymatic analysis for CYP3As and CYP2B, in microsomes and mitochondria from liver and brain tissues using the marker activities 7-benzyloxyquinoline O-debenzylase and the anthraldehyde oxidase, showed the lack of rifampicin induction in all the brain regions, unlike liver. Taken together, our results demonstrate that CYP2B22, CYP3As, and MDR1, MRP1, MRP2, and LRP transporters are all expressed, although at different extent, in the brain regions but, despite the presence of PXR and CAR, are resistant to induction indicating that the regulation of these proteins is more complex in brain than in liver. These data obtained in vivo in the brain regions and liver of pig may be of interest to human metabolism in CNS.

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Abbreviations

CYP:

Cytochrome P450

CNS:

Central nervous system

RIF:

Rifampicin

PCN:

Pregnegnolone-16α-carbonitrile

AnOx:

9-Anthraldehyde oxidase

BQD:

7-Benzyloxyquinoline O-debenzylase

GAPDH:

Glyceraldehyde 6-phosphate dehydrogenase

PXR:

Pregnane X receptor

CAR:

Constitutive androstane receptor

MDR:

Multidrug resistance

MRP:

Multidrug resistance-associated protein

LRP:

Lung resistance-related protein

BBB:

Blood–brain barrier

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Acknowledgments

We acknowledge Dr. Luigi Malvasi and the Prof. Anna Zaghini of “dip. Sanita’ Pubblica Vaterinaria e Patologia Animale” of Bologna University for pig supply and treatments.

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Authors and Affiliations

  1. Istituto di Fisiologia Clinica, CNR, Area della Ricerca CNR, via Moruzzi 1, 56100, Pisa, Italy

    Annalisa Nannelli & P. Giovanni Gervasi

  2. PCD-DMPK, GSK, Medicines Research Centre, Verona, Italy

    Francesco Rossignolo, Roberto Tolando, Paolo Rossato & Mario Pellegatti

  3. Istituto di Biologia e Biotecnologia Agraria, CNR, Via Moruzzi 1, 56100, Pisa, Italy

    Vincenzo Longo

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  1. Annalisa Nannelli
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  2. Francesco Rossignolo
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Correspondence to P. Giovanni Gervasi.

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Nannelli, A., Rossignolo, F., Tolando, R. et al. Expression and distribution of CYP3A genes, CYP2B22, and MDR1, MRP1, MRP2, LRP efflux transporters in brain of control and rifampicin-treated pigs. Mol Cell Biochem 337, 133–143 (2010). https://doi.org/10.1007/s11010-009-0292-1

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