On the mechanism of substrate/non-substrate recognition by P-glycoprotein

Mukhametov, Azat; Raevsky, Oleg A.

doi:10.1016/j.jmgm.2016.12.008

Cited by 19 publications

(12 citation statements)

References 13 publications

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“…Only cyanidin 3-glucoside could show negative result in terms of human intestinal absorption. These pieces of information may provide necessary data for designing promising and effective inhibitors of the main protease of SARS-CoV-2 in future (Cheng et al, 2012;Motohashi & Inui, 2013;Mukhametov & Raevsky, 2017).…”

Section: Discussionmentioning

confidence: 99%

A molecular modeling approach to identify effective antiviral phytochemicals against the main protease of SARS-CoV-2

Islam

Parves

Paul

et al. 2020

Journal of Biomolecular Structure and Dynamics

271

245

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Section: Discussionmentioning

confidence: 99%

A molecular modeling approach to identify effective antiviral phytochemicals against the main protease of SARS-CoV-2

Islam

Parves

Paul

et al. 2020

Journal of Biomolecular Structure and Dynamics

271

245

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“…This basal ATPase activity is commonly increased by the presence of substrate, likely as the result of conformational changes induced by substrate binding [32]. Some ABC transporters are very promiscuous, having various pockets for binding of substrates and other molecules that can act as activators or inhibitors, with the multidrug resistance ABCB1 being an excellent example [33][34][35][36]. Monitoring changes in basal ATPase activity is an effective biochemical approach to help identify substrates of ABC transporters.…”

Section: Fig 1 Heme Synthesis Pathway and Structures Of Porphyrinsmentioning

confidence: 99%

Stimulation of the human mitochondrial transporter ABCB10 by zinc-mesoporphrin

Martinez

Fendley

Saxberg

et al. 2020

Preprint

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Heme biosynthesis occurs through a series of reactions that take place within the cytoplasm and mitochondria, thus intermediates need to move across these cellular compartments. However, the specific membrane transport mechanisms involved in the process are not yet identified. The ATP-binding cassette protein ABCB10 is essential for normal heme production, as knocking down this transporter in mice is embryonically lethal and accompanied by severe anemia plus oxidative damage. The role of ABCB10 is unknown, but given its location in the inner mitochondrial membrane, it has been proposed as a candidate to export either an early heme precursor or heme. Alternatively, ABCB10 might transport a molecule important for protection against oxidative damage. To help discern between these possibilities, we decided to study the effect of heme analogs, precursors and antioxidant peptides on purified human ABCB10. Since substrate binding increases the ATP hydrolysis rate of ABC transporters, we have determined the ability of these molecules to activate purified ABCB10 reconstituted in lipid nanodiscs using ATPase measurements. Under our experimental conditions, we found that the only heme analog increasing ABCB10 ATPase activity was Zinc-mesoporphyrin. This activation of almost seventy percent was specific for ABCB10, as the ATPase activity of a negative control bacterial ABC transporter was not affected. The activation was also observed in cysteine-less ABCB10, suggesting that Zinc-mesoporphyrin’s effect did not require binding to typical heme regulatory motifs. Furthermore, our data indicate that ABCB10 was not directly activated by neither the early heme precursor delta-aminolevulinic acid nor glutathione, downsizing their relevance as putative substrates for this transporter. Although additional studies are needed to determine the physiological substrate of ABCB10, our findings reveal Zinc-mesoporphyrin as the first tool compound to directly modulate ABCB10 activity and raise the possibility that some actions of Zinc-mesoporphyrin in cellular and animal studies could be mediated by ABCB10.

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“…Additionally, Sandage et al reported that trospium did not affect in a clinically meaningful manner the pharmacokinetics of co-administered digoxin in humans. 32) One of the causes of those differences may be the difference in lipophilicity. Darifenacin has high lipophilicity, while trospium has low lipophilicity.…”

Section: Discussionmentioning

confidence: 99%

Effects of Anticholinergic Drugs Used for the Therapy of Overactive Bladder on P-Glycoprotein Activity

Wakuda

Okura

Maruyama‐Fumoto

et al. 2019

Biological & Pharmaceutical Bulletin

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We evaluated the effects of anticholinergic drugs principally used for the therapy of overactive bladder (OAB) on the activity of P-glycoprotein, an efflux transport protein, in Caco-2 cells. The time-dependent changes in the fluorescence of residual rhodamine 123, a P-glycoprotein activity marker, in the apical region of Caco-2 cells were measured in the presence of anticholinergic drugs using time-lapse confocal laser scanning microscopy. The effect of anticholinergic drugs on human P-glycoprotein ATPase activity was also measured. The fluorescence of residual rhodamine 123 in untreated Caco-2 cells decreased over time. The gradual decrease in the fluorescence was significantly inhibited by treatment with cyclosporine A, darifenacin, and trospium. In contrast, oxybutynin, N-desethyl-oxybutynin (DEOB), propiverine, and its active metabolites (M-1, M-2), imidafenacin, solifenacin, or tolterodine had little effect on the efflux of rhodamine 123. P-Glycoprotein ATPase activity was increased by darifenacin. Darifenacin and trospium reduced the rhodamine 123 transfer across the apical cell membrane. These data suggest that darifenacin and trospium interact with P-glycoprotein. Additionally, darifenacin influenced P-glycoprotein ATPase activity. These results suggest that darifenacin may be a substrate of P-glycoprotein. This study is the first paper to test simultaneously the effects of 10 anticholinergic drugs used currently for the therapy of OAB, on the P-glycoprotein.

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On the mechanism of substrate/non-substrate recognition by P-glycoprotein

Cited by 19 publications

References 13 publications

A molecular modeling approach to identify effective antiviral phytochemicals against the main protease of SARS-CoV-2

A molecular modeling approach to identify effective antiviral phytochemicals against the main protease of SARS-CoV-2

Stimulation of the human mitochondrial transporter ABCB10 by zinc-mesoporphrin

Effects of Anticholinergic Drugs Used for the Therapy of Overactive Bladder on P-Glycoprotein Activity

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