Interactions of mefloquine with ABC proteins, MRP1 (ABCC1) and MRP4 (ABCC4) that are present in human red cell membranes.

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Could someone pe-digest this for me a bit, please, too exhausted to comprehend

thanks

Nelly

Biochem Pharmacol. 2005 Aug 15;70(4):500-10.

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Interactions of mefloquine with ABC proteins, MRP1 (ABCC1) and MRP4 (ABCC4) that are present in human red cell membranes.Wu CP, Klokouzas A, Hladky SB, Ambudkar SV, Barrand MA.Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QJ, UK.Human erythrocyte membranes express the multidrug resistance-associated proteins, MRP1, MRP4 and 5, that collectively can efflux oxidised glutathione, glutathione conjugates and cyclic nucleotides. It is already known that the quinoline derivative, MK-571, is a potent inhibitor of MRP-mediated transport. We here examine whether the quinoline-based antimalarial drugs, amodiaquine, chloroquine, mefloquine, primaquine, quinidine and quinine, also interact with erythrocyte MRPs with consequences for their access to the intracellular parasites or for efflux of oxidised glutathione from infected cells. Using inside-out vesicles prepared from human erythrocytes we have shown that mefloquine and MK-571 inhibit transport of 3 microM [(3)H]DNP-SG known to be mediated by MRP1 (IC(50) 127 and 1.1 microM, respectively) and of 3.3 microM [(3)H]cGMP thought but not proven to be mediated primarily by MRP4 (IC(50) 21 and 0.41 microM). They also inhibited transport in membrane vesicles prepared from tumour cells expressing MRP1 or MRP4 and blocked calcein efflux from MRP1-overexpressing cells and BCECF efflux from MRP4-overexpressing cells. Both stimulated ATPase activity in membranes prepared from MRP1 and MRP4-overexpressing cells and inhibited activity stimulated by quercetin or PGE(1), respectively. Neither inhibited [alpha-(32)P]8-azidoATP binding confirming that the interactions are not at the ATP binding site. These results demonstrate that mefloquine and MK-571 both inhibit transport of other substrates and stimulate ATPase activity and thus may themselves be substrates for transport. But at concentrations achieved clinically mefloquine is unlikely to affect the MRP1-mediated transport of GSSG across the erythrocyte membrane.PMID: 16004972 [PubMed - in process]

[Guest guest]

Hi Nelly,

This one is full-text and maybe a little easier to understand.

http://content.febsjournal.org/cgi/content/full/268/24/6569

What they're looking at is blocking the efflux capacities of

parasitized red blood cells, with the intended effect of drowning

the parasite in its own waste products (from it's metabolism of our

heme).

I don't know if that helps or not,

> Could someone pe-digest this for me a bit, please, too

exhausted to comprehend

> thanks

>

> Nelly

>

> Biochem Pharmacol. 2005 Aug 15;70(4):500-10. Related

Articles, Links

>

>

> Interactions of mefloquine with ABC proteins, MRP1 (ABCC1) and

MRP4 (ABCC4) that are present in human red cell membranes.

>

> Wu CP, Klokouzas A, Hladky SB, Ambudkar SV, Barrand MA.

>

> Department of Pharmacology, University of Cambridge, Tennis Court

Road, Cambridge CB2 1QJ, UK.

>

> Human erythrocyte membranes express the multidrug resistance-

associated proteins, MRP1, MRP4 and 5, that collectively can efflux

oxidised glutathione, glutathione conjugates and cyclic nucleotides.

It is already known that the quinoline derivative, MK-571, is a

potent inhibitor of MRP-mediated transport. We here examine whether

the quinoline-based antimalarial drugs, amodiaquine, chloroquine,

mefloquine, primaquine, quinidine and quinine, also interact with

erythrocyte MRPs with consequences for their access to the

intracellular parasites or for efflux of oxidised glutathione from

infected cells. Using inside-out vesicles prepared from human

erythrocytes we have shown that mefloquine and MK-571 inhibit

transport of 3 microM [(3)H]DNP-SG known to be mediated by MRP1 (IC

(50) 127 and 1.1 microM, respectively) and of 3.3 microM [(3)H]cGMP

thought but not proven to be mediated primarily by MRP4 (IC(50) 21

and 0.41 microM). They also inhibited transport in membrane vesicles

prepared from tumour cells expressing MRP1 or MRP4 and blocked

calcein efflux from MRP1-overexpressing cells and BCECF efflux from

MRP4-overexpressing cells. Both stimulated ATPase activity in

membranes prepared from MRP1 and MRP4-overexpressing cells and

inhibited activity stimulated by quercetin or PGE(1), respectively.

Neither inhibited [alpha-(32)P]8-azidoATP binding confirming that

the interactions are not at the ATP binding site. These results

demonstrate that mefloquine and MK-571 both inhibit transport of

other substrates and stimulate ATPase activity and thus may

themselves be substrates for transport. But at concentrations

achieved clinically mefloquine is unlikely to affect the MRP1-

mediated transport of GSSG across the erythrocyte membrane.

>

> PMID: 16004972 [PubMed - in process]

[Guest guest]

,

Thanks for your help. Unfortunately I can't open the link. I am trying to understand what the lariam I have been taking for weekly for a couple of years with a few breaks during which I experienced a return of the bad symptoms.

Nelly

[infections] Re: Interactions of mefloquine with ABC proteins, MRP1 (ABCC1) and MRP4 (ABCC4) that are present in human red cell membranes.

Hi Nelly,This one is full-text and maybe a little easier to understand.http://content.febsjournal.org/cgi/content/full/268/24/6569What they're looking at is blocking the efflux capacities of parasitized red blood cells, with the intended effect of drowning the parasite in its own waste products (from it's metabolism of our heme).I don't know if that helps or not,> Could someone pe-digest this for me a bit, please, too exhausted to comprehend> thanks> > Nelly> > Biochem Pharmacol. 2005 Aug 15;70(4):500-10. Related Articles, Links > > > Interactions of mefloquine with ABC proteins, MRP1 (ABCC1) and MRP4 (ABCC4) that are present in human red cell membranes.> > Wu CP, Klokouzas A, Hladky SB, Ambudkar SV, Barrand MA.> > Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QJ, UK.> > Human erythrocyte membranes express the multidrug resistance-associated proteins, MRP1, MRP4 and 5, that collectively can efflux oxidised glutathione, glutathione conjugates and cyclic nucleotides. It is already known that the quinoline derivative, MK-571, is a potent inhibitor of MRP-mediated transport. We here examine whether the quinoline-based antimalarial drugs, amodiaquine, chloroquine, mefloquine, primaquine, quinidine and quinine, also interact with erythrocyte MRPs with consequences for their access to the intracellular parasites or for efflux of oxidised glutathione from infected cells. Using inside-out vesicles prepared from human erythrocytes we have shown that mefloquine and MK-571 inhibit transport of 3 microM [(3)H]DNP-SG known to be mediated by MRP1 (IC(50) 127 and 1.1 microM, respectively) and of 3.3 microM [(3)H]cGMP thought but not proven to be mediated primarily by MRP4 (IC(50) 21 and 0.41 microM). They also inhibited transport in membrane vesicles prepared from tumour cells expressing MRP1 or MRP4 and blocked calcein efflux from MRP1-overexpressing cells and BCECF efflux from MRP4-overexpressing cells. Both stimulated ATPase activity in membranes prepared from MRP1 and MRP4-overexpressing cells and inhibited activity stimulated by quercetin or PGE(1), respectively. Neither inhibited [alpha-(32)P]8-azidoATP binding confirming that the interactions are not at the ATP binding site. These results demonstrate that mefloquine and MK-571 both inhibit transport of other substrates and stimulate ATPase activity and thus may themselves be substrates for transport. But at concentrations achieved clinically mefloquine is unlikely to affect the MRP1-mediated transport of GSSG across the erythrocyte membrane.> > PMID: 16004972 [PubMed - in process]

[Guest guest]

,

I did manage to open this article. I see what you mean, just a bit beyond my (full) grasp. I can just about almost understand that there are some interesting aspects in all this but I can't quite make out what to do with it.

Story of my life these last few years

Nelly

[infections] Re: Interactions of mefloquine with ABC proteins, MRP1 (ABCC1) and MRP4 (ABCC4) that are present in human red cell membranes.

Hi Nelly,This one is full-text and maybe a little easier to understand.http://content.febsjournal.org/cgi/content/full/268/24/6569What they're looking at is blocking the efflux capacities of parasitized red blood cells, with the intended effect of drowning the parasite in its own waste products (from it's metabolism of our heme).I don't know if that helps or not,