Determination of the binding properties of the uremic toxin phenylacetic acid to human serum albumin

Saldanha, Juliana F.; Stockler‐Pinto, Milena Barcza; Soula, Hédi; Chambert, Stéphane; Fouque, Denis; Mafra, Denise; Soulage, Christophe O.

doi:10.1016/j.biochi.2016.03.002

Cited by 12 publications

(13 citation statements)

References 31 publications

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“…Phenyl acetic acid as a protein bound uremic toxin does not seem to compete for its protein binding with other major protein bound uremic toxins like p-cresyl sulfate or indoxyl sulfate [ 280 ]. Phenyl acetic acid has been linked to inhibition of inducible nitric oxide synthase (iNOS) expression [ 281 ], osteoblast proliferation and differentiation [ 282 ], enhancement of the formation of oxygen free radicals in vascular smooth muscle cells [ 283 ] and increases of inflammatory response by polymorphonuclear leukocytes [ 284 ].…”

Section: Protein Bound Compoundsmentioning

confidence: 99%

Biochemical and Clinical Impact of Organic Uremic Retention Solutes: A Comprehensive Update

Vanholder

Pletinck

Schepers

et al. 2018

Toxins

256

303

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Abstract:In this narrative review, the biological/biochemical impact (toxicity) of a large array of known individual uremic retention solutes and groups of solutes is summarized. We classified these compounds along their physico-chemical characteristics as small water-soluble compounds or groups, protein bound compounds and middle molecules. All but one solute (glomerulopressin) affected at least one mechanism with the potential to contribute to the uremic syndrome. In general, several mechanisms were influenced for each individual solute or group of solutes, with some impacting up to 7 different biological systems of the 11 considered. The inflammatory, cardio-vascular and fibrogenic systems were those most frequently affected and they are one by one major actors in the high morbidity and mortality of CKD but also the mechanisms that have most frequently been studied. A scoring system was built with the intention to classify the reviewed compounds according to the experimental evidence of their toxicity (number of systems affected) and overall experimental and clinical evidence. Among the highest globally scoring solutes were 3 small water-soluble compounds [asymmetric dimethylarginine (ADMA); trimethylamine-N-oxide (TMAO); uric acid], 6 protein bound compounds or groups of protein bound compounds [advanced glycation end products (AGEs); p-cresyl sulfate; indoxyl sulfate; indole acetic acid; the kynurenines; phenyl acetic acid;] and 3 middle molecules [β 2 -microglobulin; ghrelin; parathyroid hormone). In general, more experimental data were provided for the protein bound molecules but for almost half of them clinical evidence was missing in spite of robust experimental data. The picture emanating is one of a complex disorder, where multiple factors contribute to a multisystem complication profile, so that it seems of not much use to pursue a decrease of concentration of a single compound.Keywords: uremic toxins; uremic toxicity; uremia; Chronic Kidney Disease; CKD; cardiovascular disease; inflammation; fibrosis; patho-physiology CKD; middle molecules; protein bound uremic solutes; water-soluble uremic solutes Key Contribution: This publication contains a comprehensive overview of the current knowledge on uremic toxicity, as well as an estimation of the degree of toxicity attributed to each individual toxin, and a classification according to the degree of known toxicity.

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Section: Protein Bound Compoundsmentioning

confidence: 99%

Biochemical and Clinical Impact of Organic Uremic Retention Solutes: A Comprehensive Update

Vanholder

Pletinck

Schepers

et al. 2018

Toxins

256

303

View full text Add to dashboard Cite

show abstract

“…The interactions of some compounds tested have been examined in previous studies [18,[53][54][55][56]. The logK value of phenylacetic acid-HSA complex is between 3 and 4 [57,58], and 3M4HPAA (its hydroxy-methoxy-substituted derivative) has a similar affinity toward bovine serum albumin (logK = 3.8) [53]. HIPA (logK = 3.8), 4-HBA (no interaction), 24DHBA (logK = 3.2), and 34DHBA (logK = 3.1) formed no or poorly stable complexes with HSA [18,[54][55][56], which explains why we did not observe their relevant interactions with albumin in quenching studies.…”

Section: Discussionmentioning

confidence: 99%

Testing the Pharmacokinetic Interactions of 24 Colonic Flavonoid Metabolites with Human Serum Albumin and Cytochrome P450 Enzymes

et al. 2020

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Flavonoids are abundant polyphenols in nature. They are extensively biotransformed in enterocytes and hepatocytes, where conjugated (methyl, sulfate, and glucuronide) metabolites are formed. However, bacterial microflora in the human intestines also metabolize flavonoids, resulting in the production of smaller phenolic fragments (e.g., hydroxybenzoic, hydroxyacetic and hydroxycinnamic acids, and hydroxybenzenes). Despite the fact that several colonic metabolites appear in the circulation at high concentrations, we have only limited information regarding their pharmacodynamic effects and pharmacokinetic interactions. Therefore, in this in vitro study, we investigated the interactions of 24 microbial flavonoid metabolites with human serum albumin and cytochrome P450 (CYP2C9, 2C19, and 3A4) enzymes. Our results demonstrated that some metabolites (e.g., 2,4-dihydroxyacetophenone, pyrogallol, O-desmethylangolensin, and 2-hydroxy-4-methoxybenzoic acid) form stable complexes with albumin. However, the compounds tested did not considerably displace Site I and II marker drugs from albumin. All CYP isoforms examined were significantly inhibited by O-desmethylangolensin; nevertheless, only its effect on CYP2C9 seems to be relevant. Furthermore, resorcinol and phloroglucinol showed strong inhibitory effects on CYP3A4. Our results demonstrate that, besides flavonoid aglycones and their conjugated derivatives, some colonic metabolites are also able to interact with proteins involved in the pharmacokinetics of drugs.

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“…Moreover, CPX is predominately renally eliminated [40], hence, variable serum concentrations could be expected in patients with chronical kidney diseases and possibly, also an accumulation in the bradytrophic tendon tissue. Some of these uremic toxins, such as phenylacetic acid (PAA), are partly protein bound, by, for example, binding albumin [41]. PAA is responsible for activating several functions of polymorphonuclear leukocytes, accompanied by the expression of surface activation markers while impairing their apoptotic cell death.…”

Section: Of 18mentioning

confidence: 99%

“…Some of these uremic toxins, such as phenylacetic acid (PAA), are partly protein bound, by, for example, binding albumin [ 41 ]. PAA is responsible for activating several functions of polymorphonuclear leukocytes, accompanied by the expression of surface activation markers while impairing their apoptotic cell death.…”

Section: Introductionmentioning

confidence: 99%

Uremic Toxins and Ciprofloxacin Affect Human Tenocytes In Vitro

Popowski

Kohl

Schneider

et al. 2020

IJMS

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Tendinopathy is a rare but serious complication of quinolone therapy. Risk factors associated with quinolone-induced tendon disorders include chronic kidney disease accompanied by the accumulation of uremic toxins. Hence, the present study explored the effects of the representative uremic toxins phenylacetic acid (PAA) and quinolinic acid (QA), both alone and in combination with ciprofloxacin (CPX), on human tenocytes in vitro. Tenocytes incubated with uremic toxins +/- CPX were investigated for metabolic activity, vitality, expression of the dominant extracellular tendon matrix (ECM) protein type I collagen, cell-matrix receptor β1-integrin, proinflammatory interleukin (IL)-1β, and the ECM-degrading enzyme matrix metalloproteinase (MMP)-1. CPX, when administered at high concentrations (100 mM), suppressed tenocyte metabolism after 8 h exposure and at therapeutic concentrations after 72 h exposure. PAA reduced tenocyte metabolism only after 72 h exposure to very high doses and when combined with CPX. QA, when administered alone, led to scarcely any cytotoxic effect. Combinations of CPX with PAA or QA did not cause greater cytotoxicity than incubation with CPX alone. Gene expression of the pro-inflammatory cytokine IL-1β was reduced by CPX but up-regulated by PAA and QA. Protein levels of type I collagen decreased in response to high CPX doses, whereas PAA and QA did not affect its synthesis significantly. MMP-1 mRNA levels were increased by CPX. This effect became more pronounced in the form of a synergism following exposure to a combination of CPX and PAA. CPX was more tenotoxic than the uremic toxins PAA and QA, which showed only distinct suppressive effects.

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Determination of the binding properties of the uremic toxin phenylacetic acid to human serum albumin

Cited by 12 publications

References 31 publications

Biochemical and Clinical Impact of Organic Uremic Retention Solutes: A Comprehensive Update

Biochemical and Clinical Impact of Organic Uremic Retention Solutes: A Comprehensive Update

Testing the Pharmacokinetic Interactions of 24 Colonic Flavonoid Metabolites with Human Serum Albumin and Cytochrome P450 Enzymes

Uremic Toxins and Ciprofloxacin Affect Human Tenocytes In Vitro

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