PMID- 26903515
OWN - NLM
STAT- MEDLINE
DCOM- 20161110
LR  - 20210205
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 291
IP  - 18
DP  - 2016 Apr 29
TI  - Functional Validation of ABCA3 as a Miltefosine Transporter in Human Macrophages: 
      IMPACT ON INTRACELLULAR SURVIVAL OF LEISHMANIA (VIANNIA) PANAMENSIS.
PG  - 9638-47
LID - 10.1074/jbc.M115.688168 [doi]
AB  - Within its mammalian host, Leishmania resides and replicates as an intracellular 
      parasite. The direct activity of antileishmanials must therefore depend on 
      intracellular drug transport, metabolism, and accumulation within the host cell. 
      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 Leishmania Viannia panamensis and exposed to 
      MLF showed modulation of ABC and solute liquid carrier 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 radiolabeled MLF was significantly higher in ABCA3(KD) 
      macrophages. ABCA3(KD) resulted in increased cytotoxicity induced by MLF 
      exposure. ABCA3 gene expression inversely correlated with intracellular MLF 
      content in primary macrophages from CL patients. ABCA3(KD) 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.
CI  - (c) 2016 by The American Society for Biochemistry and Molecular Biology, Inc.
FAU - Dohmen, Luuk C T
AU  - Dohmen LC
AD  - From the Centro Internacional de Entrenamiento e Investigaciones Medicas, Cra. 
      125 # 19-225 Cali, Colombia, the Division of Pharmacoepidemiology and Clinical 
      Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 
      3508 TB Utrecht, The Netherlands.
FAU - Navas, Adriana
AU  - Navas A
AD  - From the Centro Internacional de Entrenamiento e Investigaciones Medicas, Cra. 
      125 # 19-225 Cali, Colombia.
FAU - Vargas, Deninson Alejandro
AU  - Vargas DA
AD  - From the Centro Internacional de Entrenamiento e Investigaciones Medicas, Cra. 
      125 # 19-225 Cali, Colombia.
FAU - Gregory, David J
AU  - Gregory DJ
AD  - the Molecular and Integrative Physiological Sciences, Harvard T. H. Chan School 
      of Public Health, Boston, Massachusetts 02115.
FAU - Kip, Anke
AU  - Kip A
AD  - the Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute 
      for Pharmaceutical Sciences, Utrecht University, 3508 TB Utrecht, The 
      Netherlands, the Department of Pharmacy and Pharmacology, Antoni van Leeuwenhoek 
      Hospital/Slotervaart Hospital, 1066 CX Amsterdam, The Netherlands, and.
FAU - Dorlo, Thomas P C
AU  - Dorlo TP
AD  - the Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute 
      for Pharmaceutical Sciences, Utrecht University, 3508 TB Utrecht, The 
      Netherlands, the Department of Pharmaceutical Biosciences, Uppsala University, 
      751 24 Uppsala, Sweden.
FAU - Gomez, Maria Adelaida
AU  - Gomez MA
AD  - From the Centro Internacional de Entrenamiento e Investigaciones Medicas, Cra. 
      125 # 19-225 Cali, Colombia, mgomez@cideim.org.co.
LA  - eng
GR  - D43 TW006589/TW/FIC NIH HHS/United States
GR  - R01 AI104823/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20160222
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (ABCA3 protein, human)
RN  - 0 (ATP-Binding Cassette Transporters)
RN  - 107-73-3 (Phosphorylcholine)
RN  - 53EY29W7EC (miltefosine)
SB  - IM
MH  - ATP-Binding Cassette Transporters/genetics/*metabolism
MH  - Biological Transport, Active/drug effects/genetics
MH  - Cell Line, Tumor
MH  - Gene Knockdown Techniques
MH  - Humans
MH  - Leishmania/genetics/*metabolism
MH  - Leishmaniasis/*drug therapy/genetics/metabolism
MH  - Macrophages/*metabolism/*parasitology/pathology
MH  - Phosphorylcholine/*analogs & derivatives/pharmacokinetics/pharmacology
PMC - PMC4850301
OTO - NOTNLM
OT  - ABC transporter
OT  - ABCA3
OT  - Leishmania
OT  - drug transport
OT  - host-pathogen interaction
OT  - macrophage
OT  - miltefosine
OT  - pharmacodynamics
EDAT- 2016/02/24 06:00
MHDA- 2016/11/11 06:00
PMCR- 2017/04/29
CRDT- 2016/02/24 06:00
PHST- 2015/08/26 00:00 [received]
PHST- 2016/02/24 06:00 [entrez]
PHST- 2016/02/24 06:00 [pubmed]
PHST- 2016/11/11 06:00 [medline]
PHST- 2017/04/29 00:00 [pmc-release]
AID - S0021-9258(20)43103-5 [pii]
AID - M115.688168 [pii]
AID - 10.1074/jbc.M115.688168 [doi]
PST - ppublish
SO  - J Biol Chem. 2016 Apr 29;291(18):9638-47. doi: 10.1074/jbc.M115.688168. Epub 2016 
      Feb 22.