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

Nannelli, Annalisa; Rossignolo, Francesco; Tolando, Roberto; Rossato, Paolo; Pellegatti, Mario; Longo, Vincenzo; Gervasi, Pier Giovanni

doi:10.1007/s11010-009-0292-1

Cited by 18 publications

(16 citation statements)

References 50 publications

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“…The Kp value of rifampicin (0.03, Table 1) was much lower than that of caffeine (0.5, Table 1) indicating rifampicin poor brain permeability compared to caffeine, which could be related to differences in plasma protein binding of both drugs as rifampicin has higher protein binding (88%) [48] compared to caffeine (10–37%) [49, 50]. While it is difficult to correlate plasma or brain levels of both drugs to the degree of enhanced expression of either transport protein, rifampicin and caffeine may not need to cross the BBB to upregulate LRP1or P-gp [13].…”

Section: Discussionmentioning

confidence: 99%

Enhanced Brain Amyloid-β Clearance by Rifampicin and Caffeine as a Possible Protective Mechanism Against Alzheimer's Disease

Qosa

Abuznait

Hill

et al. 2012

JAD

140

144

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Rifampicin and caffeine are widely used drugs with reported protective effect against Alzheimer’s disease (AD). However, the mechanism underlying this effect is incompletely understood. In this study, we have hypothesized that enhanced amyloid-β (Aβ) clearance from the brain across the blood-brain barrier (BBB) of wild-type mice treated with rifampicin or caffeine is caused by both drugs potential to upregulate low-density lipoprotein receptor related protein-1 (LRP1) and/or P-glycoprotein (P-gp) at the BBB. Expression studies of LRP1 and P-gp in brain endothelial cells and isolated mice brain microvessels following treatment with rifampicin or caffeine demonstrated both drugs as P-gp inducers, and only rifampicin as an LRP1 inducer. Also, brain efflux index (BEI%) studies conducted on C57BL/6 mice treated with either drug to study alterations in Aβ clearance demonstrated the BEI% of Aβ in rifampicin (82.4 ± 4.3%) and caffeine (80.4 ± 4.8%) treated mice were significantly higher than those of control mice (62.4 ±6.1%, p <0.01). LRP1 and P-gp inhibition studies confirmed the importance of both proteins to the clearance of Aβ, and that enhanced clearance following drugs treatment was caused by LRP1 and/or P-gp upregulation at the mouse BBB. Furthermore, our results provided evidence for the presence of a yet to be identified transporter/receptor that plays significant role in Aβ clearance and is upregulated by caffeine and rifampicin. In conclusion, our results demonstrated the upregulation of LRP1 and P-gp at the BBB by rifampicin and caffeine enhanced brain Aβ clearance, and this effect could explain, at least in part, the protective effect of rifampicin and caffeine against AD.

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Section: Discussionmentioning

confidence: 99%

Enhanced Brain Amyloid-β Clearance by Rifampicin and Caffeine as a Possible Protective Mechanism Against Alzheimer's Disease

Qosa

Abuznait

Hill

et al. 2012

JAD

140

144

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“…In humans, most studies have only reported the transcript expression of hPXR in brain cortex and cerebellum (Nishimura et al 2004;Miki et al 2005;Dauchy et al 2009). CAR mRNA expression has been observed in different regions of the human brain and in brain capillaries isolated from pigs and mice (Savkur et al 2003;Lamba et al 2004;Nishimura et al 2004;Dauchy et al 2008;Nannelli et al 2010). In our previous publication, hPXR protein expression was demonstrated in hCMEC/D3 cells, however the role of P-gp regulation was not investigated (Zastre et al 2009).…”

Section: (B)mentioning

confidence: 99%

“…In the brain, expression of PXR mRNA and protein have been detected in the cortex, brain capillaries and primary cultures of brain microvessel endothelial cells obtained from mice, rats and pigs (Bauer et al 2004(Bauer et al , 2006(Bauer et al , 2008Nishimura et al 2004;Narang et al 2008;Ott et al 2009;Nannelli et al 2010). In humans, most studies have only reported the transcript expression of hPXR in brain cortex and cerebellum (Nishimura et al 2004;Miki et al 2005;Dauchy et al 2009).…”

Section: (B)mentioning

confidence: 99%

Regulation of P‐glycoprotein by orphan nuclear receptors in human brain microvessel endothelial cells

Chan¹,

Hoque²,

Cummins³

et al. 2011

Journal of Neurochemistry

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J. Neurochem. (2011) 118, 163–175. Abstract In mammalian systems, pregnane X receptor (PXR) and constitutive androstane receptor (CAR) have been recognized as xenobiotic‐sensors which can up‐regulate the functional expression of drug transporters, such as P‐glycoprotein (P‐gp). In the brain, an increase in P‐gp expression can further limit drug permeability across the blood–brain barrier (BBB) and potentially reduce CNS pharmacotherapy efficacy. At present, the involvement of human PXR (hPXR) and CAR (hCAR) in the regulation of P‐gp expression at the human BBB is unknown. In this study, we investigate the role of hPXR and hCAR in the regulation of P‐gp expression using a human cerebral microvessel endothelial cell culture system. We demonstrate that activation of hPXR and hCAR by their respective ligands leads to P‐gp induction at both mRNA and protein levels, while pharmacological inhibitors of hPXR and hCAR prevent ligand‐mediated P‐gp induction. Ligand‐induced nuclear translocation of hPXR is observed, although such effect could not be demonstrated for hCAR. Furthermore, down‐regulation of hPXR and hCAR proteins using small‐interfering RNA decreased P‐gp expression. Our findings provide first evidence for P‐gp regulation by hPXR and hCAR at the human BBB and suggest insights on how to achieve selective P‐gp regulation at this site.

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“…2 | AN OVERVIEW OF NR1I2 (PXR) AND NR1I3 (CAR) NR1I2 and NR1I3 possess many structural features present in classic NRs, including the DNA-binding domain, an N-terminal AF-1 domain and a C-terminal LB ligand-binding domain D (Khorasanizadeh & Rastinejad, 2016;Mullican et al, 2013). NR1I2 and NR1I3 are 50-kDa proteins highly expressed in liver and intestine (Giessmann et al, 2004;Nannelli et al, 2010). Further studies have demonstrated that their expression pattern is more ubiquitous than initially thought, as other organs including brain, kidneys and heart also express both of these receptors (Lamba et al, 2004;Marini et al, 2007;Miki, Suzuki, Tazawa, Blumberg, & Sasano, 2005;Nannelli et al, 2010;Nishimura, Naito, & Yokoi, 2004;Savkur et al, 2003).…”

mentioning

confidence: 99%

The constitutive androstane receptor and pregnane X receptor in the brain

Torres-Vergara

Espinoza

et al. 2020

British J Pharmacology

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Since their discovery, the orphan nuclear receptors constitutive androstane receptor (CAR;NR1I3) and pregnane X receptor (PXR;NR1I2) have been regarded as master regulators of drug disposition and detoxification mechanisms. They regulate the metabolism and transport of endogenous mediators and xenobiotics in organs including the liver, intestine and brain. However, with proposals of new physiological functions for NR1I3 and NR1I2, there is increasing interest in the role of these receptors in influencing brain function. This review will summarise key findings regarding the expression and function of NR1I3 and NR1I2 in the brain, hereby highlighting the need for further research in this field.

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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

Cited by 18 publications

References 50 publications

Enhanced Brain Amyloid-β Clearance by Rifampicin and Caffeine as a Possible Protective Mechanism Against Alzheimer's Disease

Enhanced Brain Amyloid-β Clearance by Rifampicin and Caffeine as a Possible Protective Mechanism Against Alzheimer's Disease

Regulation of P‐glycoprotein by orphan nuclear receptors in human brain microvessel endothelial cells

The constitutive androstane receptor and pregnane X receptor in the brain

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