Chemistry and clinical relevance of carbohydrate degradation in drugs

Pischetsrieder, Monika; Gensberger‐Reigl, Sabrina; Atzenbeck, Lisa; Weigel, Ingrid

doi:10.1016/j.drudis.2016.06.011

Cited by 12 publications

(16 citation statements)

References 97 publications

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“…Under pathophysiological conditions 3,4-DGE has not been detected up to now, possibly due to its high reactivity (5,17).…”

mentioning

confidence: 93%

“…In contrast, an about 14-fold increase of iCGRP release over baseline was observed for 100 µM 3,4-DGE which is a 50 -fold lower concentration. The effect was also not reversible within a 5 min wash-out.CGRP-immunoreactive nociceptive nerve fibers in the parietal peritoneumIn peritoneal dialysis fluids, 3,4-DGE is found after heat sterilization and it is known to be an important reactive component that causes a variety of local and probably also systemic effects(5,19).During dialysis, the peritoneum is in direct contact with the dialysis fluids, and therefore we investigated the impact of3,4-DGE and a commercial PD fluid on nociceptors in a preparation of the parietal peritoneum. The parietal peritoneum receives sensory innervation from phrenic and spinal viscero-somatic nerves that form a dense network in the submesothelial tissue.…”

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confidence: 99%

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Reactive dicarbonyl compounds cause Calcitonin Gene-Related Peptide release and synergize with inflammatory conditions in mouse skin and peritoneum

Becker

Auditore

Pischetsrieder

et al. 2020

Journal of Biological Chemistry

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The plasmas of diabetic or uremic patients and of those receiving peritoneal dialysis treatment have increased levels of the glucose-derived dicarbonyl metabolites like methylglyoxal (MGO), glyoxal (GO), and 3-deoxyglucosone (3-DG). The elevated dicarbonyl levels can contribute to the development of painful neuropathies. Here, we used stimulated immunoreactive Calcitonin Gene–Related Peptide (iCGRP) release as a measure of nociceptor activation, and we found that each dicarbonyl metabolite induces a concentration-, TRPA1-, and Ca2+-dependent iCGRP release. MGO, GO, and 3-DG were about equally potent in the millimolar range. We hypothesized that another dicarbonyl, 3,4-dideoxyglucosone-3-ene (3,4-DGE), which is present in peritoneal dialysis (PD) solutions after heat sterilization, activates nociceptors. We also showed that at body temperatures 3,4-DGE is formed from 3-DG and that concentrations of 3,4-DGE in the micromolar range effectively induced iCGRP release from isolated murine skin. In a novel preparation of the isolated parietal peritoneum PD fluid or 3,4-DGE alone, at concentrations found in PD solutions, stimulated iCGRP release. We also tested whether inflammatory tissue conditions synergize with dicarbonyls to induce iCGRP release from isolated skin. Application of MGO together with bradykinin or prostaglandin E2 resulted in an overadditive effect on iCGRP release, whereas MGO applied at a pH of 5.2 resulted in reduced release, probably due to an MGO-mediated inhibition of transient receptor potential (TRP) V1 receptors. These results indicate that several reactive dicarbonyls activate nociceptors and potentiate inflammatory mediators. Our findings underline the roles of dicarbonyls and TRPA1 receptors in causing pain during diabetes or renal disease.

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“…Under pathophysiological conditions 3,4-DGE has not been detected up to now, possibly due to its high reactivity (5,17).…”

mentioning

confidence: 93%

mentioning

confidence: 99%

Reactive dicarbonyl compounds cause Calcitonin Gene-Related Peptide release and synergize with inflammatory conditions in mouse skin and peritoneum

Becker

Auditore

Pischetsrieder

et al. 2020

Journal of Biological Chemistry

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“…Usually, products such as peritoneal dialysis fluids (PDFs) or infusion solutions are heat-sterilized to ensure the microbiological safety. As a consequence, however, a variety of reactive GDPs are formed [1]. Most GDPs contain an αdicarbonyl moiety that reacts readily with nucleophilic side chains of amino acids such as lysine, arginine, or cysteine to form advanced glycation products (AGEs) [2][3][4].…”

Section: Introductionmentioning

confidence: 99%

“…In glucose-containing drugs, the α-dicarbonyls glucosone, 3-deoxyglucosone (3-DG), 3-deoxygalactosone (3-DGal), glyoxal, 3,4-dideoxyglucosone-3-ene (3,, and methylglyoxal (MGO) were identified ( Fig. 1) [1,16]. In total, up to 450 μM GDPs with α-dicarbonyl structure were detected in commercial PDFs [17].…”

Section: Introductionmentioning

confidence: 99%

Metal cations promote α-dicarbonyl formation in glucose-containing peritoneal dialysis fluids

et al. 2020

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Heat sterilization of peritoneal dialysis fluids (PDFs) leads to the formation of glucose degradation products (GDPs), which impair long-term peritoneal dialysis. The current study investigated the effects of metal ions, which occur as trace impurities in the fluids, on the formation of six major α-dicarbonyl GDPs, namely glucosone, glyoxal, methylglyoxal, 3-deoxyglucosone, 3-deoxygalactosone, and 3,4-dideoxyglucosone-3-ene. The chelation of metal ions by 2-[bis[2-[bis(carboxymethyl)amino]ethyl]amino]acetic acid (DTPA) during sterilization significantly decreased the total GDP content (585 μM vs. 672 μM), mainly due to the decrease of the glucose-oxidation products glucosone (14 μM vs. 61 μM) and glyoxal (3 μM vs. 11 μM), but also of methylglyoxal (14 μM vs. 31 μM). The glucose-dehydration products 3-deoxyglucosone, 3-deoxygalactosone, and 3,4-dideoxyglucosone-3-ene were not significantly affected by chelation of metal ions. Additionally, PDFs were spiked with eleven different metal ions, which were detected as traces in commercial PDFs, to investigate their influence on GDP formation during heat sterilization. Iron(II), manganese(II), and chromium(III) had the highest impact increasing the formation of glucosone (1.2–1.5 fold increase) and glyoxal (1.3–1.5 fold increase). Nickel(II) and vanadium(III) further promoted the formation of glyoxal (1.3 fold increase). The increase of the pH value of the PDFs from pH 5.5 to a physiological pH of 7.5 resulted in a decreased formation of total GDPs (672 μM vs 637 μM). These results indicate that the adjustment of metal ions and the pH value may be a strategy to further decrease the content of GDPs in PDFs.

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“…Furthermore, the formation of AGEs resulting from carbohydrate degradation has also been addressed as a problem in drug safety, e.g. in heat sterilization of glucose-containing infusion fluids (Schalwijk et al 1999;Pischetsrieder et al 2016).…”

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confidence: 99%

High complexity of toxic reactions: parallels between products of oxidative stress and advanced glycation end products

Bolt

2020

Arch Toxicol

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Chemistry and clinical relevance of carbohydrate degradation in drugs

Cited by 12 publications

References 97 publications

Reactive dicarbonyl compounds cause Calcitonin Gene-Related Peptide release and synergize with inflammatory conditions in mouse skin and peritoneum

Reactive dicarbonyl compounds cause Calcitonin Gene-Related Peptide release and synergize with inflammatory conditions in mouse skin and peritoneum

Metal cations promote α-dicarbonyl formation in glucose-containing peritoneal dialysis fluids

High complexity of toxic reactions: parallels between products of oxidative stress and advanced glycation end products

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