Multidrug resistance-associated protein 4 (MRP4) controls ganciclovir intracellular accumulation and contributes to ganciclovir-induced neutropenia in renal transplant patients
Jazyk angličtina Země Nizozemsko Médium print-electronic
Typ dokumentu časopisecké články, přehledy, práce podpořená grantem
PubMed
27402191
DOI
10.1016/j.phrs.2016.07.012
PII: S1043-6618(16)30429-7
Knihovny.cz E-zdroje
- Klíčová slova
- Cytomegalovirus, Ganciclovir, Membrane transporters, Multidrug resistance-associated protein 4, Pharmacogenetics, Transplantation,
- MeSH
- antivirové látky * škodlivé účinky farmakokinetika terapeutické užití MeSH
- cytomegalovirové infekce prevence a kontrola MeSH
- dospělí MeSH
- ganciklovir * škodlivé účinky farmakokinetika MeSH
- HEK293 buňky MeSH
- jednonukleotidový polymorfismus MeSH
- Jurkat buňky MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- neutropenie chemicky indukované genetika metabolismus MeSH
- proteiny spojené s mnohočetnou rezistencí k lékům genetika metabolismus MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- transplantace ledvin MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- Názvy látek
- ABCC4 protein, human MeSH Prohlížeč
- antivirové látky * MeSH
- ganciklovir * MeSH
- proteiny spojené s mnohočetnou rezistencí k lékům MeSH
Ganciclovir (GCV) is the cornerstone of cytomegalovirus prevention and treatment in transplant patients. It is associated with problematic adverse hematological effects in this population of immunosuppressed patients, which may lead to dose reduction thus favoring resistance. GCV crosses the membranes of cells, is activated by phosphorylation, and then stops the replication of viral DNA. Its intracellular accumulation might favor host DNA polymerase inhibition, hence toxicity. Following this hypothesis, we investigated the association between a selected panel of membrane transporter polymorphisms and the evolution of neutrophil counts in n=174 renal transplant recipients. An independent population of n=96 renal transplants served as a replication and experiments using HEK293T-transfected cells were performed to validate the clinical findings. In both cohorts, we found a variant in ABCC4 (rs11568658) associated with decreased neutrophil counts following valganciclovir (GCV prodrug) administration (exploratory cohort: β±SD=-0.68±0.28, p=0.029; replication cohort: β±SD=-0.84±0.29, p=0.0078). MRP4-expressing cells showed decreased GCV accumulation as compared to negative control cells (transfected with an empty vector) (-61%; p<0.0001). The efflux process was almost abolished in cells expressing MRP4 rs11568658 variant protein. Molecular dynamic simulations of GCV membrane crossing showed a preferred location of the drug just beneath the polar head group region, which supports its interaction with efflux transporters.
CHU Bordeaux Service de Néphrologie Transplantation Dialyse F 33000 Bordeaux France
Univ Limoges LCSN Faculté de Pharmacie F 87025 Limoges France
Univ Limoges UMR 850 F 87000 Limoges France; INSERM UMR 850 F 87000 Limoges France
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