Inhibition of diamine oxidase from porcine kidney by pentamidine and other aminoguanidine compounds

Cubría, J.C.; Ordóñez, David; Alvarez-Bujidos, M.L.; Negro, A.; Ortiz, Ana I.

doi:10.1016/0305-0491(91)90217-2

Cited by 7 publications

(5 citation statements)

References 18 publications

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“…Also, pentamidine must not compete with polyamines for transport. In addition, these results contradict the hypothesis that pentamidine inhibits polyamine metabolism (10,23).…”

Section: Discussioncontrasting

confidence: 79%

“…Molecular similarities of P. carinii to the fungi include not only the rRNA genes (14, 30) but also many other genes, such as the dihydrofolate reductase (13) and thymidylate synthase (15) genes. An authoritative analysis of the rRNA phylogeny, including appropriate outgroups, indicates that P. carinii diverged from (or within) the Ascomycetes lineage very early in fungal evolution, such that P. carinii is as closely related to S. cerevisiae as it is to any other known fungus (5).Pentamidine has been implicated in the inhibition of a bewildering variety of cellular processes in various systems (10,12,18,23,25,26). Much recent work has focused upon the interactions of pentamidine with DNA (9,12,16 organism.…”

mentioning

confidence: 99%

“…Pentamidine has been implicated in the inhibition of a bewildering variety of cellular processes in various systems (10,12,18,23,25,26). Much recent work has focused upon the interactions of pentamidine with DNA (9,12,16 organism.…”

mentioning

confidence: 99%

“…We investigated the pentamidine sensitivity of growth on a number of other energy sources (Table 1). Only on energy sources that required mitochondrial respiratory function was wild-type yeast growth inhibited by concentrations of pentamidine below 10 ,ug/ml.…”

mentioning

confidence: 99%

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Effects of pentamidine isethionate on Saccharomyces cerevisiae

Ludewig

Williams

et al. 1994

Antimicrob Agents Chemother

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We used Saccharomyces cerevisiae as a model system in which to examine the mechanism of action of the anti-Pneumocystis drug pentamidine. Pentamidine at low concentrations inhibited S. cerevisiae growth on nonfermentable carbon sources (50%o inhibitory concentration [IC50] of 1.25 ,ug/ml in glycerol). Pentamidine inhibited growth on fermentable energy sources only at much higher concentrations (IC50 of 250 ,ug/ml in glucose). Inhibition at low pentamidine concentrations in glycerol was due to cytostatic activity rather than cytotoxic or mutagenic activity. Pentamidine also rapidly inhibited respiration by intact yeast cells, although inhibitory concentrations were much higher than those inhibitory to growth (IC50 of 100 ,ug/ml for respiration).Pentamidine also induced petite mutations, although only at concentrations much higher than those required for growth inhibition. These results suggest that a function essential for respiratory growth is inhibited by pentamidine and that pentamidine affects mitochondrial processes. We propose the hypothesis that the primary cellular target of pentamidine in S. cerevisiae is the mitochondrion.Pentamidine is widely used for the prophylaxis and treatment of Pneumocystis carinii pneumonia in AIDS patients (32). Pentamidine is also used to treat African trypanosomiasis and leishmaniasis (33). Unfortunately, pentamidine is not always effective, and it frequently causes undesirable side effects (21). Although pentamidine has been used in clinical settings for 40 years, uncertainty remains about its mechanism of action. In addition, widespread use of pentamidine as a prophylactic provokes concern over the evolution of pentamidine resistance in P. carinii (32,35). Resistance to pentamidine, both natural and acquired, occurs in trypanosomes (11,17).Although one can investigate the effects of pentamidine on P. carinii by using immunocompromised animals (20) or an in vitro microculture test system (6), detailed studies are hindered by the inability to culture P. carinii in vitro. Therefore, we have identified a model organism, Saccharomyces cerevisiae, that is sensitive to pentamidine under appropriate conditions and that can be readily manipulated by sophisticated biological techniques.In phylogenetic terms, S. cerevisiae is an appropriate model for P. carinii. Considerable molecular and morphologic evidence indicates that P. carinii is a fungus (29). Molecular similarities of P. carinii to the fungi include not only the rRNA genes (14, 30) but also many other genes, such as the dihydrofolate reductase (13) and thymidylate synthase (15) genes. An authoritative analysis of the rRNA phylogeny, including appropriate outgroups, indicates that P. carinii diverged from (or within) the Ascomycetes lineage very early in fungal evolution, such that P. carinii is as closely related to S. cerevisiae as it is to any other known fungus (5).Pentamidine has been implicated in the inhibition of a bewildering variety of cellular processes in various systems (10,12,18,23,25,26). Much recent work has f...

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“…Also, pentamidine must not compete with polyamines for transport. In addition, these results contradict the hypothesis that pentamidine inhibits polyamine metabolism (10,23).…”

Section: Discussioncontrasting

confidence: 79%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Effects of pentamidine isethionate on Saccharomyces cerevisiae

Ludewig

Williams

et al. 1994

Antimicrob Agents Chemother

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“…Meanwhile, aminoguanidine, a known inhibitor of DAO, inhibited porcine DAO greater than 80 % at 100 μM in the presence of putrescine (100 μM) as the substrate. Previously, Cubria et al [57] reported that phenformin, a biguanide and a predecessor of metformin, inhibited diamine oxidase with K i of 4 mM. Furthermore, the reported K M value of putrescine using porcine diamine oxidase is 0.35 mM [58], which is within the error of our measurements.…”

Section: Resultssupporting

confidence: 83%

Prediction and validation of enzyme and transporter off-targets for metformin

Yee

Lin

Merski

et al. 2015

J Pharmacokinet Pharmacodyn

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Metformin, an established first-line treatment for patients with type 2 diabetes, has been associated with gastrointestinal (GI) adverse effects that limit its use. Histamine and serotonin have potent effects on the GI tract. The effects of metformin on histamine and serotonin uptake were evaluated in cell lines overexpressing several amine transporters (OCT1, OCT3 and SERT). Metformin inhibited histamine and serotonin uptake by OCT1, OCT3 and SERT in a dose-dependent manner, with OCT1-mediated amine uptake being most potently inhibited (IC50 = 1.5 mM). A chemoinformatics-based method known as Similarity Ensemble Approach predicted diamine oxidase (DAO) as an additional intestinal target of metformin, with an E-value of 7.4 × 10−5. Inhibition of DAO was experimentally validated using a spectrophotometric assay with putrescine as the substrate. The Ki of metformin for DAO was measured to be 8.6 ± 3.1 mM. In this study, we found that metformin inhibited intestinal amine transporters and DAO at concentrations that may be achieved in the intestine after therapeutic doses. Further studies are warranted to determine the relevance of these interactions to the adverse effects of metformin on the gastrointestinal tract.

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From caffeine to fish waste: amine compounds present in food and drugs and their interactions with primary amine oxidase

Olivieri

Rico²,

Khiari³

et al. 2011

J Neural Transm

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Tissue bound primary amine oxidase (PrAO) and its circulating plasma-soluble form are involved, through their catalytic activity, in important cellular roles, including the adhesion of lymphocytes to endothelial cells during various inflammatory conditions, the regulation of cell growth and maturation, extracellular matrix deposition and maturation and glucose transport. PrAO catalyses the oxidative deamination of several xenobiotics and has been linked to vascular toxicity, due to the generation of cytotoxic aldehydes. In this study, a series of amines and aldehydes contained in food and drugs were tested via a high-throughput assay as potential substrates or inhibitors of bovine plasma PrAO. Although none of the compounds analyzed were found to be substrates for the enzyme, a series of molecules, including caffeine, the antidiabetics phenformin and tolbutamide and the antimicrobial pentamidine, were identified as PrAO inhibitors. Although the inhibition observed was in the millimolar and micromolar range, these data show that further work will be necessary to elucidate whether the interaction of ingested biogenic or xenobiotic amines with PrAO might adversely affect its biological roles.

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Inhibition of diamine oxidase from porcine kidney by pentamidine and other aminoguanidine compounds

Cited by 7 publications

References 18 publications

Effects of pentamidine isethionate on Saccharomyces cerevisiae

Effects of pentamidine isethionate on Saccharomyces cerevisiae

Prediction and validation of enzyme and transporter off-targets for metformin

From caffeine to fish waste: amine compounds present in food and drugs and their interactions with primary amine oxidase

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