Protein kinase C-dependent regulation of human hepatic drug transporter expression

Mayati, Abdullah; Vée, Marc Le; Moreau, A; Jouan, Elodie; Bucher, Simon; Stieger, Bruno; Denizot, Claire; Parmentier, Yannick; Fardel, Olivier

doi:10.1016/j.bcp.2015.10.007

Cited by 14 publications

(22 citation statements)

References 63 publications

(57 reference statements)

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“…PKCα activation is also associated with induced P-gp expression in non-cancerous tissues such as the liver of diabetic rats, suggesting a link between hyperglycemia and P-gp overexpression via PKC [153]. MDR1/ABCB1 mRNA expression has additionally been shown to be transiently induced by PMA in primary human hepatocytes [18]. However, inhibition of PKCα isoform enhances P-gp expression and the survival of cultured LoVo human colon adenocarcinoma cells to doxorubicin exposure [154].…”

Section: Pkcs-dependent Regulation Of Drug Transporter Expressionmentioning

confidence: 99%

“…ENT1 suppression by high glucose in rat cardiac fibroblasts is mediated by aPKCζ [156]. Finally, PMA treatment of primary human hepatocytes, that induces MDR1 / ABCB1 mRNA expression as reported above, concomitantly reduces those of OATP1B1, OATP1B3, OATP2B1, NTCP, OCT1 and BSEP and enhances that of MRP3, without impairing those of MRP2 and BCRP [18]. Such PKCs-dependent changes in transporter expression have been hypothesized to be linked to epithelial–mesenchymal transition triggered by PKC activation in hepatic cells like human hepatoma HepaRG cells [18].…”

Section: Pkcs-dependent Regulation Of Drug Transporter Expressionmentioning

confidence: 99%

“…Activation of PKCs also modulates drug transporter localization in plasma membrane of polarized cells such as hepatocytes [15,16]. PKC activation additionally impairs messenger ribonucleic acid (mRNA) and/or protein levels of drug transporters [17,18]. As graphically summarized in Figure 1, PKCs can thus theoretically affect different aspects of drug transporter regulation, e.g., transcriptional or translational mechanisms controlling transporter expression, membrane insertion or internalization processes and phosphorylation status of transporters.…”

Section: Introductionmentioning

confidence: 99%

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Protein Kinases C-Mediated Regulations of Drug Transporter Activity, Localization and Expression

Mayati

Moreau

Vée

et al. 2017

IJMS

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Drug transporters are now recognized as major actors in pharmacokinetics, involved notably in drug–drug interactions and drug adverse effects. Factors that govern their activity, localization and expression are therefore important to consider. In the present review, the implications of protein kinases C (PKCs) in transporter regulations are summarized and discussed. Both solute carrier (SLC) and ATP-binding cassette (ABC) drug transporters can be regulated by PKCs-related signaling pathways. PKCs thus target activity, membrane localization and/or expression level of major influx and efflux drug transporters, in various normal and pathological types of cells and tissues, often in a PKC isoform-specific manner. PKCs are notably implicated in membrane insertion of bile acid transporters in liver and, in this way, are thought to contribute to cholestatic or choleretic effects of endogenous compounds or drugs. The exact clinical relevance of PKCs-related regulation of drug transporters in terms of drug resistance, pharmacokinetics, drug–drug interactions and drug toxicity remains however to be precisely determined. This issue is likely important to consider in the context of the development of new drugs targeting PKCs-mediated signaling pathways, for treating notably cancers, diabetes or psychiatric disorders.

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Section: Pkcs-dependent Regulation Of Drug Transporter Expressionmentioning

confidence: 99%

Section: Pkcs-dependent Regulation Of Drug Transporter Expressionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Protein Kinases C-Mediated Regulations of Drug Transporter Activity, Localization and Expression

Mayati

Moreau

Vée

et al. 2017

IJMS

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“…Importantly, these stimulatory effects increased the affinities of the substrates to the OATPs, indicating allosteric modulation. Besides direct interactions with the transport protein, the function of OATPs can also be regulated at the transcriptional, translational, or even post-translational level [6, 16, 17]. Furthermore, there is the potential for protein-protein interactions that could influence transporter function, similar to what has been shown for drug-metabolizing enzymes [18].…”

Section: Introductionmentioning

confidence: 99%

Organic anion transporting polypeptide 1B3 can form homo- and hetero-oligomers

2017

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OATP1B3 is a 12 transmembrane domain protein expressed at the basolateral membrane of human hepatocytes where it mediates the uptake of numerous drugs and endogenous compounds. Previous western blot results suggest the formation of OATP1B3 multimers. In order to better understand the function of OATP1B3 under normal physiological conditions, we investigated its oligomerization status. We transiently transfected OATP1B3 with a C-terminal His-, FLAG- or HA-tag in HEK293 cells and used co-immunoprecipitation and a Proximity Ligation Assay to detect interactions between the different constructs. All three constructs retained similar transport rates as wild-type OATP1B3. Immunofluorescence experiments indicated that in contrast to wild-type, His- and FLAG-tagged OATP1B3, where the C-terminal end is on the cytoplasmic side of the membrane, the C-terminal end of HA-tagged OATP1B3 is extracellular. After cross-linking, anti-FLAG antibodies were able to pull down FLAG-tagged OATP1B3 (positive control) and co-transfected His- or HA-tagged OATP1B3, demonstrating the formation of homo-oligomers and suggesting that the C-terminal part is not involved in oligomer formation. We confirmed co-localization of His- and FLAG-tagged OATP1B3 in transfected HEK293 cells with the Proximity Ligation Assay. Transport studies with a non-functional OATP1B3 mutant suggest that the individual subunits and not the whole oligomer are the functional units in the homo-oligomers. In addition, we also detected OATP1B3-FLAG co-localization with OATP1B1-His or NTCP-His, suggesting that OATP1B3 also hetero-oligomerizes with other transport proteins. Using the Proximity Ligation Assay with transporter specific antibodies, we demonstrate close association of OATP1B3 with NTCP in frozen human liver tissue. These findings demonstrate that OATP1B3 can form homo- and hetero-oligomers and suggest a potential co-regulation of the involved transporters.

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“…Specific ready-to-use gene primers for -adrenergic receptor isoforms were purchased from Qiagen (Hilden, Germany). Other gene specific primers were exactly as previously described (Mayati et al, 2015) or are listed in Table S2. Amplification curves of the PCR products were…”

Section: Rna Isolation and Analysismentioning

confidence: 99%

β2-adrenergic receptor-mediated in vitro regulation of human hepatic drug transporter expression by epinephrine

Mayati

Moreau

Denizot

et al. 2017

European Journal of Pharmaceutical Sciences

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The catecholamine epinephrine is known to repress expression of hepatic drug metabolizing enzymes such as cytochromes P-450. The present study was designed to determine whether epinephrine may also target expression of main hepatic drug transporters, that play a major role in liver detoxification and are commonly coordinately regulated with drug detoxifying enzymes. Treatment of primary human hepatocytes with 10μM epinephrine for 24h repressed mRNA expression of various transporters, such as the sinusoidal influx transporters NTCP, OATP1B1, OATP2B1, OAT2, OAT7 and OCT1 and the efflux transporters MRP2, MRP3 and BSEP, whereas it induced that of MDR1, but failed to alter that of BCRP. Most of these changes in transporter mRNA levels were also found in epinephrine-exposed human highly-differentiated hepatoma HepaRG cells, which additionally exhibited reduced protein expression of OATP2B1 and MRP3, increased expression of P-glycoprotein and decreased transport activity of NTCP, OATPs and OCT1. Epinephrine effects towards transporter mRNA expression in human hepatocytes were next shown to be correlated to those of the selective β2-adrenoreceptor (ADR) agonist fenoterol, of the adenylate cyclase activator forskolin and of the cAMP analogue 8-bromo-cAMP. In addition, the non-selective β-ADR antagonist carazolol and the selective β2-ADR antagonist ICI-118,551, unlike the α-ADR antagonist phentolamine, suppressed epinephrine-mediated repressions of transporter mRNA expression. Taken together, these data indicate that epinephrine regulates in vitro expression of main hepatic drug transporters in a β2-ADR/adenylate cyclase/cAMP-dependent manner. Hepatic drug transport appears therefore as a target of the β2-adrenergic system, which may have to deserve attention for drugs interacting with β2-ADRs.

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Protein kinase C-dependent regulation of human hepatic drug transporter expression

Cited by 14 publications

References 63 publications

Protein Kinases C-Mediated Regulations of Drug Transporter Activity, Localization and Expression

Protein Kinases C-Mediated Regulations of Drug Transporter Activity, Localization and Expression

Organic anion transporting polypeptide 1B3 can form homo- and hetero-oligomers

β2-adrenergic receptor-mediated in vitro regulation of human hepatic drug transporter expression by epinephrine

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