Inhibition of the Multidrug Efflux Pump in Isolated Hepatocyte Couplets by Immunosuppressants Fk506 and Cyclosporine

Takeguchi, Noriaki; Ichimura, Kazuyoshi; Koike, Masahiko; Matsui, Wakako; Kashiwagura, Tadashi; Katsumasa, Kawahara

doi:10.1097/00007890-199303000-00033

Cited by 56 publications

(20 citation statements)

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“…Both verapamil and cyclosporin A have been shown to inhibit P-glycoprotein-mediated transport across hepatocyte membranes in multiple model systems (25)(26)(27)(28)(29)(30)(31)(32)(33). The effects of verapamil are not likely secondary to changes in intracellular Ca 2ϩ since verapamil at the doses used does not change intracellular Ca 2ϩ in isolated hepatocytes or alter passive Ca 2ϩ transport across membrane vesicles (34,35).…”

Section: Discussionmentioning

confidence: 99%

Hepatocellular ATP-binding Cassette Protein Expression Enhances ATP Release and Autocrine Regulation of Cell Volume

Roman¹,

Wang²,

Lidofsky³

et al. 1997

Journal of Biological Chemistry

157

165

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Extracellular ATP is a potent signaling factor that modulates a variety of cellular functions through the activation of P 2 purinergic receptors in the plasma membrane. These receptors are widely distributed among different liver cell types, including hepatocytes, cholangiocytes, macrophages, and endothelial cells, but the physiologic roles have not been fully defined. Cells release ATP in response to both osmotic and mechanical stimuli, and one mechanism may involve opening of a channel-like pathway (1, 2). In respiratory epithelia, ATP release stimulated by cytosolic cAMP activates outwardly rectified Cl Ϫ channels coupled to P 2U receptors and enhances Cl Ϫ secretion (3).Recent studies in a model liver cell line support an alternative pathway where increases in cell volume induce conductive ATP efflux. In these cells, removal of extracellular ATP or P 2 receptor blockade prevents both Cl Ϫ channel activation and volume recovery (1). These findings suggest functional interactions between ATP release, P 2 receptor stimulation, and Cl Ϫ channel opening in epithelial secretion and volume regulation.Members of the ATP-binding cassette (ABC) 1 protein family are likely to be relevant to this volume regulatory pathway for two reasons. First, while the molecular basis for the transmembrane ATP conductance has not been established, heterologous expression or up-regulation of ABC family members in some cell models is associated with enhanced electrodiffusional ATP release. In cystic fibrosis respiratory epithelia, cAMP fails to stimulate channel-mediated ATP efflux, a response that is present in native epithelia; CFTR gene transfer restores the ATP conductance (3, 4). In other cell lines, ATP release is proportional to the expression of mammalian and Drosophila Mdr1 P-glycoproteins (5, 6). Second, in some but not all cell types, Mdr1 P-glycoproteins regulate swelling-activated Cl Ϫ currents (I Cl-swell ). Effects include enhancement of I Cl-swell and endowment of Cl Ϫ channel sensitivity to protein kinase C (mdr1 gene transfer) and increase in I Cl-swell for a given hypotonic stress (P-glycoprotein overexpression) (7,8). The cellular mechanisms involved in these responses and the implications for other cell types have yet to be clarified.In hepatocytes, P-glycoproteins transport both amphipathic compounds and phospholipids across canalicular membranes into bile (9, 10). However, the functions of multiple other ABC members present in liver cells are unknown. In light of the putative association of certain ABC proteins with channelmediated ATP and Cl Ϫ transport, we sought to investigate the role of hepatocellular ABC proteins in these processes. Findings in rat HTC hepatoma cells were compared with those in a selected population of HTC cells (HTC-R) that overexpress both endogenous and novel Mdr proteins (11). These studies demonstrate that inhibition of P-glycoprotein transport prevents recovery from swelling and that overexpression of Mdr proteins is associated with enhanced ATP release, volume recovery, and cell surv...

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Section: Discussionmentioning

confidence: 99%

Hepatocellular ATP-binding Cassette Protein Expression Enhances ATP Release and Autocrine Regulation of Cell Volume

Roman¹,

Wang²,

Lidofsky³

et al. 1997

Journal of Biological Chemistry

157

165

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“…CsA is a well-known potent P-gp inhibitor [15,16]. Therefore, coadministration of CsA may enhance the brain distribution of DOM, resulting in DOM-induced parkinsonism.…”

Section: Introductionmentioning

confidence: 99%

Potentiation of domperidone‐induced catalepsy by a P‐glycoprotein inhibitor, cyclosporin A

Tsujikawa

Dan

Nogawa

et al. 2003

Biopharm & Drug Disp

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The distribution of domperidone (DOM), a peripheral dopamine D(2) receptor antagonist, to the brain is restricted by P-glycoprotein (P-gp) at the blood-brain barrier (BBB) and for this reason, DOM rarely causes parkinsonian symptoms, such as extrapyramidal side effects (EPS), unlike other dopamine D(2) antagonists. In this study, we aimed to investigate whether cyclosporin A (CsA), a P-gp inhibitor, potentiates EPS induced by DOM. The intensity of EPS was assessed in terms of the duration of catalepsy in mice. D(1), D(2) and mACh receptor occupancies at the striatum were measured in vivo and in vitro. Moreover, the distribution of DOM to the brain was investigated by using an in situ brain perfusion technique. The intensity of DOM-induced catalepsy was significantly potentiated by the coadministration of CsA. The in vivo occupancies of D(1), D(2) and mACh receptors, as well as the brain distribution of DOM, were increased by CsA. These results suggest that CsA increases the brain distribution of DOM by inhibiting P-gp at the BBB, and potentiates catalepsy by increasing the occupancies of the D(1) and D(2) receptors. The risk of DOM-induced parkinsonism may be enhanced by the coadministration of CsA.

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“…Changes of biliary lipid secretion by CsA have been reported to inhibit biliary output of both cholesterol and phospholipid [9], cholesterol alone [ 3 ] , and phospholipid alone [2,27]. Although the exact mechanism of biliary lipids secretion remains unclear, it has been shown that CsA inhibits the activity of the multidrug efflux pump (P-glycoproteins) dose-dependently, but TCR is less effective in the isolated hepatocyte couplets [29]. P-glycoproteins are active transporters that effluxe a variety of structurally diverse xenobiotics.…”

Section: Discussionmentioning

confidence: 99%

Influence of tacrolimus on bile acid and lipid composition in continuously drained bile using a rat model.

Mizuta¹,

Kobayashi²,

Uchida³

et al. 1999

Transplant Int

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Cholestatic effects have been reported for cyclosporine (CsA), but information is still limited for tacrolimus (TCR). The purpose of this study was to investigate the influence of TCR on biliary bile acid and lipid composition as compared with CsA, using a continuously bile-drained rat model. Adult male Wistar rats received TCR (0.4 mg/kg, 1 mg/kg, and 4 mg/kg) or CsA (2.5 mg/kg, 10 mg/kg, and 25 mg/kg) by intramuscular injection (i. m.) daily for 10 days.

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Inhibition of the Multidrug Efflux Pump in Isolated Hepatocyte Couplets by Immunosuppressants Fk506 and Cyclosporine

Cited by 56 publications

References 0 publications

Hepatocellular ATP-binding Cassette Protein Expression Enhances ATP Release and Autocrine Regulation of Cell Volume

Hepatocellular ATP-binding Cassette Protein Expression Enhances ATP Release and Autocrine Regulation of Cell Volume

Potentiation of domperidone‐induced catalepsy by a P‐glycoprotein inhibitor, cyclosporin A

Influence of tacrolimus on bile acid and lipid composition in continuously drained bile using a rat model.

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