PMID- 30422662
OWN - NLM
STAT- MEDLINE
DCOM- 20191118
LR  - 20211204
IS  - 1543-8392 (Electronic)
IS  - 1543-8384 (Linking)
VI  - 16
IP  - 1
DP  - 2019 Jan 7
TI  - Impact of Zn(2+) on ABC Transporter Function in Intact Isolated Rat Brain 
      Microvessels, Human Brain Capillary Endothelial Cells, and in Rat in Vivo.
PG  - 305-317
LID - 10.1021/acs.molpharmaceut.8b00987 [doi]
AB  - ABC transporters act as efflux pumps, thereby influencing the pharmacokinetics 
      and efficacy of many drugs. Zinc (Zn) is an essential trace element contributing 
      to cellular growth and differentiation. It is increasingly recognized as an 
      intracellular messenger. The present study aims at investigating the impact of 
      Zn(2+) on the function and regulation of ABC transporters at the blood-brain 
      barrier (BBB). ABC transporter function was first studied in isolated rat brain 
      capillaries. Zn(2+) rapidly stimulated the activity of the multidrug 
      resistance-related protein 2 (Mrp2), p-glycoprotein (P-gp), and breast cancer 
      resistance protein (Bcrp). These short-term effects were independent of 
      transporter de novo synthesis but based on Zn(2+) triggering intracellular 
      signaling to stimulate basal transport activity. Studies focused on Mrp2 and P-gp 
      showed that Zn(2+) induced signaling through an endothelin receptor type B 
      (ET(B))/nitric oxide synthase (NOS)/protein kinase C (PKC) pathway and caused, 
      specifically, an activation of the isoform PKCalpha. Studies revealed signaling 
      through the phosphatidylinositol 3-kinase (PI3K)/mechanistic target of rapamycin 
      (mTOR) pathway, as well as induction of the downstream target serum- and 
      glucocorticoid-inducible kinase 1 (SGK1). Short-term effects of Zn(2+) were also 
      demonstrated in human hCMEC/D3 cells. An initial in vivo study in rats suggested 
      enhanced P-gp transport activity at the BBB due to elevated Zn(2+) plasma levels. 
      This work provides the first evidence for Zn(2+) being a regulator of basal ABC 
      transporter activity at the BBB, driving a rapid and nongenomic stimulation of 
      transport function.
FAU - Zaremba, Alexander
AU  - Zaremba A
AD  - Institute of Pharmacy and Molecular Biotechnology , Ruprecht-Karls University , 
      69120 Heidelberg , Germany.
FAU - Helm, Frieder
AU  - Helm F
AD  - Institute of Pharmacy and Molecular Biotechnology , Ruprecht-Karls University , 
      69120 Heidelberg , Germany.
FAU - Fricker, Gert
AU  - Fricker G
AUID- ORCID: 0000-0003-3894-961X
AD  - Institute of Pharmacy and Molecular Biotechnology , Ruprecht-Karls University , 
      69120 Heidelberg , Germany.
LA  - eng
PT  - Journal Article
DEP - 20181129
PL  - United States
TA  - Mol Pharm
JT  - Molecular pharmaceutics
JID - 101197791
RN  - 0 (ABCG2 protein, human)
RN  - 0 (ATP Binding Cassette Transporter, Subfamily B, Member 1)
RN  - 0 (ATP Binding Cassette Transporter, Subfamily G, Member 2)
RN  - 0 (ATP-Binding Cassette Transporters)
RN  - 0 (EDNRB protein, human)
RN  - 0 (Immediate-Early Proteins)
RN  - 0 (Neoplasm Proteins)
RN  - 0 (Receptor, Endothelin B)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase)
RN  - EC 2.7.1.137 (Phosphatidylinositol 3-Kinase)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (serum-glucocorticoid regulated kinase)
RN  - EC 2.7.11.13 (Protein Kinase C)
RN  - J41CSQ7QDS (Zinc)
SB  - IM
MH  - ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism
MH  - ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism
MH  - ATP-Binding Cassette Transporters/genetics/*metabolism
MH  - Animals
MH  - Biological Transport/drug effects
MH  - Blood-Brain Barrier/drug effects
MH  - Brain/*metabolism
MH  - Endothelial Cells/drug effects/metabolism
MH  - Endothelium, Vascular/cytology/drug effects/metabolism
MH  - Humans
MH  - Immediate-Early Proteins/metabolism
MH  - Neoplasm Proteins/metabolism
MH  - Nitric Oxide Synthase/metabolism
MH  - Phosphatidylinositol 3-Kinase/metabolism
MH  - Protein Kinase C/metabolism
MH  - Protein Serine-Threonine Kinases/metabolism
MH  - Rats
MH  - Receptor, Endothelin B/metabolism
MH  - Signal Transduction/drug effects
MH  - Zinc/*pharmacology
OTO - NOTNLM
OT  - ABC transporters
OT  - P-glycoprotein
OT  - blood-brain barrier
OT  - zinc
EDAT- 2018/11/14 06:00
MHDA- 2019/11/19 06:00
CRDT- 2018/11/14 06:00
PHST- 2018/11/14 06:00 [pubmed]
PHST- 2019/11/19 06:00 [medline]
PHST- 2018/11/14 06:00 [entrez]
AID - 10.1021/acs.molpharmaceut.8b00987 [doi]
PST - ppublish
SO  - Mol Pharm. 2019 Jan 7;16(1):305-317. doi: 10.1021/acs.molpharmaceut.8b00987. Epub 
      2018 Nov 29.