Inhibitory effects of prostaglandin A1 on membrane transport of folates mediated by both the reduced folate carrier and ATP-driven exporters

Assaraf, Yehuda G.; Sierra, Esteban E.; Babani, Solomon; Goldman, I. David

doi:10.1016/s0006-2952(99)00227-0

Cited by 17 publications

(13 citation statements)

References 26 publications

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“…For example, investigators in our group recently demonstrated that prostaglandin A 1 (PGA 1 ), which is a charged organic anion at physiologic pH, is a potent noncompetitive inhibitor of RFC-mediated transport of MTX (K i ϭ 21 M) (65). Our current study revealed that the monovalent anion SSZ also displays an interaction with the RFC.…”

Section: Discussionmentioning

confidence: 48%

Sulfasalazine is a potent inhibitor of the reduced folate carrier: Implications for combination therapies with methotrexate in rheumatoid arthritis

Jansen¹,

Heijden²,

Oerlemans³

et al. 2004

Arthritis & Rheumatism

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Objective. To investigate whether interactions of sulfasalazine (SSZ) with reduced folate carrier (RFC), the dominant cell membrane transporter for natural folates and methotrexate (MTX), may limit the efficacy of combination therapy with MTX and SSZ in patients with rheumatoid arthritis. Conclusion. At clinically relevant plasma concentrations, interactions of SSZ with RFC provide a biochemical rationale for 2 important clinical observations: 1) the onset of (sub)clinical folate deficiency during SSZ treatment, and 2) the lack of additivity/synergism of the combination of SSZ and MTX when these diseasemodifying antirheumatic drugs are administered simultaneously. Thus, when considering use of these drugs in combination therapies, the present results provide a rationale both for the use of folate supplementation and for spacing administration of these drugs over time.

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Section: Discussionmentioning

confidence: 48%

Sulfasalazine is a potent inhibitor of the reduced folate carrier: Implications for combination therapies with methotrexate in rheumatoid arthritis

Jansen¹,

Heijden²,

Oerlemans³

et al. 2004

Arthritis & Rheumatism

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“…Hence, MRPs always oppose the concentrative transport mechanisms for folates such as RFC; and therefore, their functional expression is an important factor in the very low concentrations of free antifolates that accumulate in cells. In fact, a variety of agents, such as probenecid, vincristine, VM-26, VP-16, and PGA 1 depress the efflux and augment the free level of MTX in cells (Fyfe and Goldman, 1973;Sirotnak et al, 1981c;Fry et al, 1982a;Yalowich et al, 1982;Assaraf et al, 1999). This has been associated with enhanced accumulation of antifolate polyglutamates (Fry et al, 1982a;Yalowich et al, 1982) and in some cases enhanced antifolate activity in vivo (Sirotnak et al, 1981aKhokhar et al, 2001).…”

Section: Mrps As a Factor In The Limited Concentrative Transport Of mentioning

confidence: 99%

Resistance to antifolates

2003

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“…Early studies showed that the efflux of cAMP from erythrocytes is inhibited by several prostaglandins (23,24), and we have recently found that the cellular efflux of cGMP by both MRP4 and MRP5 can also be inhibited by prostaglandins (25). Moreover, PGA 1 inhibits the ATP-dependent efflux of methotrexate, another MRP4 substrate (21), from Chinese hamster ovary cells (26). Based on these observations, we investigated the interaction between members of the MRP family and prostaglandins.…”

mentioning

confidence: 94%

The human multidrug resistance protein MRP4 functions as a prostaglandin efflux transporter and is inhibited by nonsteroidal antiinflammatory drugs

Reid

Wielinga

Zelcer

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

471

371

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Prostaglandins are involved in a wide variety of physiological and pathophysiological processes, but the mechanism of prostaglandin release from cells is not completely understood. Although poorly membrane permeable, prostaglandins are believed to exit cells by passive diffusion. We have investigated the interaction between prostaglandins and members of the ATP-binding cassette (ABC) transporter ABCC [multidrug resistance protein (MRP)] family of membrane export pumps. In inside-out membrane vesicles derived from insect cells or HEK293 cells, MRP4 catalyzed the time-and ATP-dependent uptake of prostaglandin E 1 (PGE1) and PGE2. In contrast, MRP1, MRP2, MRP3, and MRP5 did not transport PGE 1 or PGE 2. The MRP4-mediated transport of PGE1 and PGE2 displayed saturation kinetics, with K m values of 2.1 and 3.4 M, respectively. Further studies showed that PGF 1␣, PGF2␣, PGA1, and thromboxane B 2 were high-affinity inhibitors (and therefore presumably substrates) of MRP4. Furthermore, several nonsteroidal antiinflammatory drugs were potent inhibitors of MRP4 at concentrations that did not inhibit MRP1. In cells expressing the prostaglandin transporter PGT, the steady-state accumulation of PGE 1 and PGE2 was reduced proportional to MRP4 expression. Inhibition of MRP4 by an MRP4-specific RNA interference construct or by indomethacin reversed this accumulation deficit. Together, these data suggest that MRP4 can release prostaglandins from cells, and that, in addition to inhibiting prostaglandin synthesis, some nonsteroidal antiinflammatory drugs might also act by inhibiting this release. P rostaglandins are key mediators in the regulation of many physiological processes. They are involved in inflammatory responses and tumorigenesis, and their synthesis and metabolism are tightly regulated (1). The first step in prostaglandin synthesis is the production of arachidonic acid, which is released from membrane lipid primarily by cytosolic phospholipase A 2 (1). Arachidonic acid is then oxidized to the intermediate prostaglandin H 2 (PGH 2 ) by PGH synthases, also known as cyclooxygenase (COX)-1 and -2, and the recently identified COX-3 (2). These enzymes are known clinically as the targets of aspirin and other nonsteroidal antiinf lammatory drugs (NSAIDs) (3). Moreover, several recent studies have shown a link between COX-2 expression and carcinogenesis. Prostaglandins are overproduced by a variety of tumors, leading to the suggested prophylactic use of COX-2 inhibitors to decrease the incidence of colon cancer (4, 5). After COX-mediated synthesis, PGH 2 is further converted by tissue-specific prostaglandin synthases into PGE 2 , PGF 2␣ , PGD 2 , prostacyclin, or thromboxane B 2 , the biologically active molecules (1).Prostaglandins are formed and secreted by most cells, and act as autocrine-or paracrine-signaling molecules. In many cases they exert their effects extracellularly via interaction with a family of G protein-coupled membrane receptors (reviewed in ref. 6), although some prostaglandins interact with the nuclear horm...

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Inhibitory effects of prostaglandin A1 on membrane transport of folates mediated by both the reduced folate carrier and ATP-driven exporters

Cited by 17 publications

References 26 publications

Sulfasalazine is a potent inhibitor of the reduced folate carrier: Implications for combination therapies with methotrexate in rheumatoid arthritis

Sulfasalazine is a potent inhibitor of the reduced folate carrier: Implications for combination therapies with methotrexate in rheumatoid arthritis

Resistance to antifolates

The human multidrug resistance protein MRP4 functions as a prostaglandin efflux transporter and is inhibited by nonsteroidal antiinflammatory drugs

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