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Sökning: onr:"swepub:oai:DiVA.org:uu-279087" > Functional Validati...

LIBRIS Formathandbok  (Information om MARC21)
FältnamnIndikatorerMetadata
00003328naa a2200349 4500
001oai:DiVA.org:uu-279087
003SwePub
008160229s2016 | |||||||||||000 ||eng|
0247 a https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-2790872 URI
0247 a https://doi.org/10.1074/jbc.M115.6881682 DOI
040 a (SwePub)uu
041 a engb eng
042 9 SwePub
072 7a ref2 swepub-contenttype
072 7a art2 swepub-publicationtype
1001 a Dohmen, Luuk C T4 aut
2451 0a Functional Validation of ABCA3 as a Miltefosine Transporter in Human Macrophages :b Impact on Intracellular Survival of Leishmania (Viannia) panamensis
264 1c 2016
338 a print2 rdacarrier
520 a Within its mammalian host, Leishmania resides and replicates as an intracellular parasite. The direct activity of antileishmanials must therefore depend on host intracellular drug transport, metabolism and accumulation. In this study, we explored the role of human macrophage transporters in the intracellular accumulation and antileishmanial activity of miltefosine (MLF), the only oral drug available for the treatment of visceral and cutaneous leishmaniasis (CL). Membrane transporter gene expression in primary human macrophages infected in vitro with L.V. panamensis and exposed to MLF showed modulation of ABC and SLC transporters gene transcripts. Among these, ABCA3, a lipid transporter, was significantly induced after exposure to MLF and this induction was confirmed in primary macrophages from CL patients. Functional validation of MLF as a substrate for ABCA3 was performed by shRNA gene knockdown (KD) in THP-1 monocytes. Intracellular accumulation of radiolabelled-MLF was significantly higher in ABCA3KD macrophages. ABCA3KD resulted in increased cytotoxicity induced by MLF exposure. ABCA3 gene expression inversely correlated with intracellular MLF content in primary macrophages from CL patients. ABCA3KD reduced parasite survival during macrophage infection with an L.V. panamensis strain exhibiting low in vitro susceptibility to MLF. Confocal microscopy showed ABCA3 to be located in the cell membrane of resting macrophages, and in intracellular compartments in L.V. panamensis infected cells. These results provide evidence of ABCA3 as an MLF efflux transporter in human macrophages, and support its role in the direct antileishmanial effect of this alkylphosphocholine drug.
650 7a MEDICIN OCH HÄLSOVETENSKAPx Medicinska och farmaceutiska grundvetenskaperx Farmaceutiska vetenskaper0 (SwePub)301012 hsv//swe
650 7a MEDICAL AND HEALTH SCIENCESx Basic Medicinex Pharmaceutical Sciences0 (SwePub)301012 hsv//eng
7001 a Navas, Adriana4 aut
7001 a Vargas, Deninson Alejandro4 aut
7001 a Gregory, David J4 aut
7001 a Kip, Anke4 aut
7001 a Dorlo, Thomas P Cu Uppsala universitet,Institutionen för farmaceutisk biovetenskap,Pharmacometrics Group4 aut0 (Swepub:uu)thodo249
7001 a Gomez, Maria Adelaida4 aut
7102 a Uppsala universitetb Institutionen för farmaceutisk biovetenskap4 org
7730 t Journal of Biological Chemistryg 291:18, s. 9638-9647q 291:18<9638-9647x 0021-9258x 1083-351X
8564 8u https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-279087
8564 8u https://doi.org/10.1074/jbc.M115.688168

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