Transport of the areca nut alkaloid arecaidine by the human proton-coupled amino acid transporter 1 (hPAT1)

Voigt, Valerie; Laug, Linda; Zebisch, Katja; Thondorf, Iris; Markwardt, Fritz; Brandsch, Matthias

doi:10.1111/jphp.12006

Cited by 11 publications

(4 citation statements)

References 38 publications

(99 reference statements)

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“…Hence, while it is not possible to replay the evolutionary tape, it is entirely reasonable that many of the several hundred human uptake transporters [69] were in fact selected, at least in part, precisely to transport exogenous secondary metabolites. Indeed, mammalian transporters are well known for their ability to transport many exogenous natural product drugs, e.g., SLCO family members for penicillins [179,180], cephalosporins [181,182], tetracycline [183], caffeine, theobromine and theophylline [184] and digoxin [185], SLC22 for berberine [186] and protoberberines [187], morphine [188], erythromycin [189] and theophylline [189], SLC15 for penicillins and cephalosporins [190,191], SLC6 family (norepinephrine transporters) [192] for ephedrine derivatives [193], and SLC36 for arecaidine (an active constituent of the Areca nut, often wrongly referred to as the betel nut) [194].…”

Section: Natural Products That Are Nutrients or Bioactive Drugs Must mentioning

confidence: 99%

Consensus rank orderings of molecular fingerprints illustrate the most genuine similarities between marketed drugs and small endogenous human metabolites, but highlight exogenous natural products as the most important ‘natural’ drug transporter substrates

O’Hagan¹,

Kell

2017

ADMET DMPK

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We compare several molecular fingerprint encodings for marketed, small molecule drugs, and assess how their rank order varies with the fingerprint in terms of the Tanimoto similarity to the most similar endogenous human metabolite as taken from Recon2. For the great majority of drugs, the rank order varies very greatly depending on the encoding used, and also somewhat when the Tanimoto similarity (TS) is replaced by the Tversky similarity. However, for a subset of such drugs, amounting to some 10 % of the set and a Tanimoto similarity of ~0.8 or greater, the similarity coefficient is relatively robust to the encoding used. This leads to a metric that, while arbitrary, suggests that a Tanimoto similarity of 0.75-0.8 or greater genuinely does imply a considerable structural similarity of two molecules in the drug-endogenite space. Although comparatively few (<10 % of) marketed drugs are, in this sense, robustly similar to an endogenite, there is often at least one encoding with which they are genuinely similar (e.g. TS > 0.75). This is referred to as the Take Your Pick Improved Cheminformatic Analytical Likeness or TYPICAL encoding, and on this basis some 66 % of drugs are within a TS of 0.75 to an endogenite.We next explicitly recognise that natural evolution will have selected for the ability to transport dietary substances, including plant, animal and microbial ‘secondary’ metabolites, that are of benefit to the host. These should also be explored in terms of their closeness to marketed drugs. We thus compared the TS of marketed drugs with the contents of various databases of natural products. When this is done, we find that some 80 % of marketed drugs are within a TS of 0.7 to a natural product, even using just the MACCS encoding. For patterned and TYPICAL encodings, 80 % and 98 % of drugs are within a TS of 0.8 to (an endogenite or) an exogenous natural product. This implies strongly that it is these exogeneous (dietary and medicinal) natural products that are more to be seen as the ‘natural’ substrates of drug transporters (as is recognised, for instance, for the solute carrier SLC22A4 and ergothioneine). This novel analysis casts an entirely different light on the kinds of natural molecules that are to be seen as most like marketed drugs, and hence potential transporter substrates, and further suggests that a renewed exploitation of natural products as drug scaffolds would be amply rewarded.

show abstract

Section: Natural Products That Are Nutrients or Bioactive Drugs Must mentioning

confidence: 99%

Consensus rank orderings of molecular fingerprints illustrate the most genuine similarities between marketed drugs and small endogenous human metabolites, but highlight exogenous natural products as the most important ‘natural’ drug transporter substrates

O’Hagan¹,

Kell

2017

ADMET DMPK

View full text Add to dashboard Cite

show abstract

“…Hence, while it is not possible to replay the evolutionary tape, it is entirely reasonable that many of the several hundred human uptake transporters [68] were in fact selected, at least in part, precisely to transport exogenous secondary metabolites. Indeed, mammalian transporters are well known for their ability to transport many exogenous natural product drugs, e.g., SLCO family members for penicillins [178; 179], cephalosporins [180; 181], tetracycline [182], caffeine, theobromine and theophylline [183] and digoxin [184], SLC22 for berberine [185] and protoberberines [186], morphine [187], erythromycin [188] and theophylline [188], SLC15 for penicillins and cephalosporins [189; 190], SLC6 family (norepinephrine transporters) [191] for ephedrine derivatives [192], and SLC36 for arecaidine (an active constituent of the Areca nut, often wrongly referred to as the betel nut) [193].…”

Section: Natural Products That Are Nutrients or Bioactive Drugs Must mentioning

confidence: 99%

Consensus rank orderings of molecular fingerprints illustrate the ‘most genuine’ similarities between marketed drugs and small endogenous human metabolites, but highlight exogenous natural products as the most important ‘natural’ drug transporter substrates

O’Hagan

Kell

2017

Preprint

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We compare several molecular fingerprint encodings for marketed, small molecule drugs, and assess how their rank order varies with the fingerprint in terms of the Tanimoto similarity to the most similar endogenous human metabolite as taken from Recon2. For the great majority of drugs, the rank order varies very greatly depending on the encoding used, and also somewhat when the Tanimoto similarity (TS) is replaced by the Tversky similarity. However, for a subset of such drugs, amounting to some 10% of the set and a Tanimoto similarity of ~0.8 or greater, the similarity coefficient is relatively robust to the encoding used. This leads to a metric that, while arbitrary, suggests that a Tanimoto similarity of 0.75-0.8 or greater genuinely does imply a considerable structural similarity of two molecules in the drug-endogenite space. Although comparatively few (<10% of) marketed drugs are, in this sense, robustly similar to an endogenite, there is often at least one encoding with which they are genuinely similar (e.g. TS > 0.75). This is referred to as the Take Your Pick Improved Cheminformatic Analytical Likeness or TYPICAL encoding, and on this basis some 66% of drugs are within a TS of 0.75 to an endogenite.We next explicitly recognise that natural evolution will have selected for the ability to transport dietary substances, including plant, animal and microbial 'secondary' metabolites, that are of benefit to the host. These should also be explored in terms of their closeness to marketed drugs. We thus compared the TS of marketed drugs with the contents of various databases of natural products. When this is done, we find that some 80% of marketed drugs are within a TS of 0.7 to a natural product, even using just the MACCS encoding. For patterned and TYPICAL encodings, 80% and 98% of drugs are within a TS of 0.8 to (an endogenite or) an exogenous natural product. This implies strongly that it is these exogeneous (dietary and medicinal) natural products that are more to be seen as the 'natural' substrates of drug transporters (as is recognised, for instance, for the solute carrier SLC22A4 and ergothioneine). This novel analysis casts an entirely different light on the kinds of natural molecules that are to be seen as most like marketed drugs, and hence potential transporter substrates, and further suggests that a renewed exploitation of natural products as drug scaffolds would be amply rewarded.

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“…Pinang dilaporkan mengandung senyawa alkaloid arekolin yang memiliki aktivitas antihiperglikemik. Arekolin dapat masuk ke dalam sel-sel otot rangka dengan berikatan pada PAT-1 (proton-coupled amino acid transporter-1) (Voigt et al 2013;Jensen et al 2014). Selanjutnya, senyawa alkaloid arekolin mampu menginduksi pengambilan 2-deoksiglukosa dalam L6 myotube melalui peningkatan ekspresi GLUT4 dan gen-gen yang terlibat dalam jalur PI3K terkait proses translokasi GLUT4 (Prabhakar & Doble 2011).…”

Section: Pendahuluanunclassified

Efektivitas Ekstrak Etanol Biji Pinang Terhadap Densitas GLUT4 pada Sel-Sel Otot Rangka Mencit yang Terinduksi Hiperglikemia

Sari¹,

Ridwan²

2017

JSDH

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Betel nut (Areca catechu) was proven to have antihyperglycemic activity through increased PI3K pathway in the GLUT4 translocation in cells. However, research on the ethanol extract of betel nut in Indonesia is still limited. The main problem in this study was whether the ethanol extract of betel nut could improve glucose tolerance in a two-hour postprandial period and whether the ethanol extract of betel nut could induce GLUT4 translocation in skeletal muscle cells of mice induced hyperglycemia. Glucose tolerance test results showed that treatment of the ethanol extract of betel nut for 24 days with all doses tested: P50,100,150,200 and 250 mg/kg body weight could improve glucose tolerance in a two-hour postprandial period. The protein electrophoresis of that fasting and one hour postprandial state treatments resulted an increase in GLUT4/βActin density ratio of P250 group compared to negative and positive controls. In this case, GLUT4/βActin density ratio of P100,P200 and P250 were higher than that GLUT4/βActin density ratio of P50 and P150. Increased in GLUT4/βActin density ratio showed enhancement of the GLUT4 in skeletal muscle cells in fasting and one hour postprandial state after treated with ethanol extract of betel nut.

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Transport of the areca nut alkaloid arecaidine by the human proton-coupled amino acid transporter 1 (hPAT1)

Abstract: We conclude that hPAT1 transports arecaidine, guvacine and isoguvacine across the apical membrane of enterocytes and that hPAT1 might be responsible for the intestinal absorption of these drug candidates.

Cited by 11 publications

References 38 publications

Consensus rank orderings of molecular fingerprints illustrate the most genuine similarities between marketed drugs and small endogenous human metabolites, but highlight exogenous natural products as the most important ‘natural’ drug transporter substrates

Consensus rank orderings of molecular fingerprints illustrate the most genuine similarities between marketed drugs and small endogenous human metabolites, but highlight exogenous natural products as the most important ‘natural’ drug transporter substrates

Consensus rank orderings of molecular fingerprints illustrate the ‘most genuine’ similarities between marketed drugs and small endogenous human metabolites, but highlight exogenous natural products as the most important ‘natural’ drug transporter substrates

Efektivitas Ekstrak Etanol Biji Pinang Terhadap Densitas GLUT4 pada Sel-Sel Otot Rangka Mencit yang Terinduksi Hiperglikemia

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