Synergistic transport of a fluorescent coumarin probe marks coumarins as pharmacological modulators of Organic anion-transporting polypeptide, OATP3A1

Bakos, Éva; Tusnády, Gábor; Német, Orsolya; Patik, Izabel; Magyar, Csaba; Németh, Krisztina; Kele, Péter; Özvegy‐Laczka, Csilla

doi:10.1016/j.bcp.2020.114250

Cited by 12 publications

(22 citation statements)

References 52 publications

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“…Expression of OATP3A1 variants was confirmed by Western blot, as described in Bakos et al (2020). Whole-cell lysates of HEK-293 (5 μg) were loaded onto 7.5% SDS/PAGE gels and transferred onto PVDF membranes.…”

Section: Immunoblot Detection Of Oatp3a1 Variantsmentioning

confidence: 99%

“…SLCO3A1 mRNA has been detected in numerous fetal and adult tissues (Tamai et al, 2000), while at the protein level, OATP3A1 expression has been shown in the central nervous system (choroid plexus and neurons (Huber et al, 2007)) as well as in the testis (Huber et al, 2007), breast (Kindla et al, 2011) and heart (Atilano-Roque and Joy, 2017). Physiological substrates of OATP3A1 encompass estrone-3-sulfate (E1S), prostaglandin (PG) E1 and E2, vasopressin, and thyroxine (Bakos et al, 2020, Huber et al, 2007, Tamai et al, 2000. In addition to these endogenous substances, OATP3A1 is also able to transport drugs.…”

Section: Introductionmentioning

confidence: 99%

“…However, because of the lack of exhaustive studies, the list of substrates and inhibitors of OATP3A1 may be incomplete. Recently, we have identified various coumarin-based dyes as substrates of OATP3A1 (Bakos et al, 2020). These dyes, in addition to the previously described indicator, fluorescein (Atilano-Roque and Joy, 2017, Patik et al, 2015), can help in identifying further molecules interacting with OATP3A1.…”

Section: Introductionmentioning

confidence: 99%

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Cloning and characterization of a novel functional organic anion transporting polypeptide 3A1 isoform highly expressed in the human brain and testis

et al. 2022

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Organic anion transporting polypeptide 3A1 (OATP3A1, encoded by the SLCO3A1 gene) is a prostaglandin, oligopeptide, and steroid/thyroid hormone transporter with wide tissue distribution, expressed, e.g., in the human brain and testis. Although the physiological importance of OATP3A1 has not yet been clarified, based on its expression pattern, substrate recognition, and evolutionary conservation, OATP3A1 is a potential pharmacological target. Previously, two isoforms of OATP3A1, termed as V1 and V2, have been characterized. Here, we describe the cloning and functional characterization of a third isoform, OATP3A1_V3. The mRNA of isoform V3 is formed by alternative splicing and results in an OATP3A1 protein with an altered C-terminus compared to isoforms V1 and V2. Based on quantitative PCR, we demonstrate the widespread expression of SLCO3A1_V3 mRNA in human organs, with the highest expression in the brain and testis. By generation of an isoform V3-specific antibody and immunostaining, we show that the encoded protein is expressed in the human choroid plexus, neurons, and both germ and Sertoli cells of the testis. Moreover, we demonstrate that in contrast to isoform V1, OATP3A1_V3 localizes to the apical membrane of polarized MDCKII cells. Using HEK-293 cells engineered to overexpress OATP3A1_V3, we verify the protein’s functionality and identify dehydroepiandrosterone sulfate as a novel OATP3A1 substrate. Based on their distinct expression patterns but overlapping functions, OATP3A1 isoforms may contribute to transcellular (neuro)steroid transport in the central nervous system.

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Section: Immunoblot Detection Of Oatp3a1 Variantsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cloning and characterization of a novel functional organic anion transporting polypeptide 3A1 isoform highly expressed in the human brain and testis

et al. 2022

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“…Specific to OATP3A1 is the transport of arachidonic acid, and similar to OATP1C1 and OATP2A1, it has more discretesubstrate specificity and perhaps also narrowed to endogenous compounds [194,195]. However, it needs to be remembered that the lack of reported drug substrate and inhibitors may also be due to the limited number of studies that have been carried out with less studied OATP subtypes [206].…”

Section: Organic Anion Transporting Family (Slco/slc21a)mentioning

confidence: 99%

Increased/Targeted Brain (Pro)Drug Delivery via Utilization of Solute Carriers (SLCs)

et al. 2022

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Membrane transporters have a crucial role in compounds’ brain drug delivery. They allow not only the penetration of a wide variety of different compounds to cross the endothelial cells of the blood–brain barrier (BBB), but also the accumulation of them into the brain parenchymal cells. Solute carriers (SLCs), with nearly 500 family members, are the largest group of membrane transporters. Unfortunately, not all SLCs are fully characterized and used in rational drug design. However, if the structural features for transporter interactions (binding and translocation) are known, a prodrug approach can be utilized to temporarily change the pharmacokinetics and brain delivery properties of almost any compound. In this review, main transporter subtypes that are participating in brain drug disposition or have been used to improve brain drug delivery across the BBB via the prodrug approach, are introduced. Moreover, the ability of selected transporters to be utilized in intrabrain drug delivery is discussed. Thus, this comprehensive review will give insights into the methods, such as computational drug design, that should be utilized more effectively to understand the detailed transport mechanisms. Moreover, factors, such as transporter expression modulation pathways in diseases that should be taken into account in rational (pro)drug development, are considered to achieve successful clinical applications in the future.

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“…OATP3A1 (known as SLCO3A1 ) is expressed in multiple tissues ( 6 , 7 , 8 , 9 , 10 , 11 , 12 ) including the liver and functions as a membrane transporter mediating estrone-3-sulfate, prostaglandins E1 and E2, and thyroxine uptake ( 12 , 13 , 14 , 15 ). Previously, we have shown that OATP3A1 regulates the transport of BA efflux in cholestasis ( 6 ).…”

mentioning

confidence: 99%

Tumor necrosis factor α upregulates the bile acid efflux transporter OATP3A1 via multiple signaling pathways in cholestasis

Li¹,

Wang²,

Cheng³

et al. 2022

Journal of Biological Chemistry

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Synergistic transport of a fluorescent coumarin probe marks coumarins as pharmacological modulators of Organic anion-transporting polypeptide, OATP3A1

Cited by 12 publications

References 52 publications

Cloning and characterization of a novel functional organic anion transporting polypeptide 3A1 isoform highly expressed in the human brain and testis

Cloning and characterization of a novel functional organic anion transporting polypeptide 3A1 isoform highly expressed in the human brain and testis

Increased/Targeted Brain (Pro)Drug Delivery via Utilization of Solute Carriers (SLCs)

Tumor necrosis factor α upregulates the bile acid efflux transporter OATP3A1 via multiple signaling pathways in cholestasis

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