Yeast

It is discovered that in Saccharomyces cerevisiae, furfural and HMF lead to the formation of cytoplasmic mRNP granules and the reduction of bulk translation activity. SG formation and translation initiation are notably suppressed when furfural and HMF are combined. Cytoplasmic mRNP granules can be induced by furfural and HMF. HMF also gradually lowers the polysome fraction while simultaneously raising the 80S monosome fraction[1].

Absorption, Distribution and Excretion
This study determined the 5-hydroxymethylfurfural (HMF) content in Norwegian foods and estimated HMF dietary intake in 53 volunteers using a 24-hour dietary recall method. Estimated HMF intake was correlated with urinary excretion of 5-hydroxymethyl-2-furanoic acid (HMFA). Coffee, prunes, stout, canned peaches, and raisins had the highest HMF content. The 95th percentiles of estimated daily HMF dietary intake and 24-hour urinary HMFA excretion were 27.6 mg and 28.6 mg, respectively. Coffee, dried fruit, honey, and alcohol were identified as independent determinants of urinary HMFA excretion. Most participants' estimated HMF intake was lower than their urinary HMFA excretion. Nevertheless, a significant correlation was found between estimated HMF intake and urinary HMF levels (r=0.57, P<0.001)...
...In a small human study involving seven healthy volunteers, researchers investigated the urinary excretion of unmetabolized 5-hydroxymethylfurfural. After ingesting 20 grams of plum jam containing 24 mg of 5-hydroxymethylfurfural, subjects excreted an average of 163 micrograms over 6 hours, equivalent to 0.75% of the ingested 5-hydroxymethylfurfural.

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Metabolism/Metabolites
5-Hydroxymethylfurfural (HMF) is produced in carbohydrate-rich foods via acid-catalyzed dehydration and the Maillard reaction of reducing sugars. HMF is present in a variety of foods, with levels measured in mg/kg. HMF is primarily metabolized to 5-hydroxymethyl-2-furanoic acid (HMFA), but it may also generate unknown amounts of the mutagenic 5-sulfonylmethylfurfural (SMF), making HMF potentially harmful to humans…
5-Hydroxymethylfurfural (HMF) is generated during the acidification or heating of carbohydrates. It is found in high concentrations in many foods. HMF is inactive in standard genotoxicity tests, but it can be metabolized to the chemically active intermediate 5-sulfonylmethylfurfural (SMF), which is mutagenic and carcinogenic. …Direct injection of SMF into mice resulted in extensive acute necrosis and protein casts in the proximal tubules, which was the main toxic effect. Since proximal tubular cells actively mediate the excretion of many organic anions, we hypothesized that SMF entering cells via transport proteins might be the cause of this selective organ toxicity. To test this hypothesis, we used human embryonic kidney cells (HEK293) stably expressing human OAT1 or OAT3. SMF is a competitive inhibitor of hOAT1 on the uptake of para-aminohippuric acid and hOAT3 on estrone sulfate, with Ki values of 225 μM and 1.5 mM, respectively. Furthermore, cells expressing hOAT1 and hOAT3 showed initial SMF uptake rates 5.2-fold and 3.1-fold higher than control HEK293 cells, respectively. Similarly, cells expressing hOAT1 and hOAT3 were significantly more sensitive to SMF cytotoxicity than control cells, and this sensitivity could be reduced by adding the OAT inhibitor probenecid. In summary, these results indicate that OAT1 and OAT3 mediate SMF entry into proximal renal tubular cells, potentially contributing to SMF-induced nephrotoxicity. 5-Hydroxymethylfurfural (HMF) is produced from reducing sugars via acid-catalyzed dehydration and Maillard reaction, and is abundant in various foods. Studies have shown that HMF can induce the formation of abnormal colonic crypt foci in rats, as well as the development of cutaneous papillomas and hepatocellular adenomas in mice. HMF was inactive in in vitro genotoxicity assays using a standard activation system, but it can be activated as a mutagen by sulfonyltransferases. Its product, 5-sulfomethylfurfural (SMF), is more carcinogenic than HMF. To date, SMF has not been detected in in vivo biotransformation studies of HMF in humans and animals. This study reports the pharmacokinetic characteristics of HMF and SMF in FVB/N mice. A sensitive method for the quantitative analysis of HMF and SMF using multiple reaction monitoring (MLMS/MS) was designed. Following intravenous injection of SMF (4.4 μmol/kg body weight), its elimination kinetics in plasma followed first-order kinetics (t_1/2 = 7.9 min). Following intravenous injection of HMF (793 μmol/kg body weight), its elimination kinetics in plasma followed biphasic kinetics (t_1/2 for the initial elimination phase and t_1/2 for the terminal elimination phase were 1.7 min and 28 min, respectively); the volume of distribution in the central compartment was approximately equivalent to the total body fluid volume. Peak SMF plasma concentrations were observed at the initial sampling time (2.5 min after HMF administration). Based on these kinetic data, it was estimated that 452 to 551 ppm of the initial HMF dose was converted to SMF and entered the bloodstream. Additional SMF may react with cellular structures at the site of generation and is therefore ignored in this equilibrium…
5-Hydroxymethyl-2-furfural (HMF) is a major product of sugar degradation and is found in food and parenteral nutrition solutions. Labeled [(14)C]HMF was synthesized by dehydration of [(14C)]fructose on an ion exchange resin and administered to rats orally (po) and intravenously (iv). Radioactive metabolic equilibrium showed that HMF or its metabolites were rapidly excreted in the urine after 24 hours with a recovery rate of 95–100%. Literature reports that in some cases, up to 50% of HMF may remain in the body. HMF is completely converted into two metabolites, identified by nuclear magnetic resonance (NMR) and mass spectrometry (MS) as 5-hydroxymethyl-2-furfural acid and N-(5-hydroxymethyl-2-furfural)glycine. Following high-dose HMF administration, its clearance rate was also rapid, but the amount of glycine conjugates generated was correspondingly reduced. Whole-body animal autoradiography confirmed that radioactive material was detectable in the liver shortly after administration, but was mainly distributed in the kidneys and bladder. The only significant difference between oral and intravenous administration was that the intravenous administration group had higher levels of radioactive material in the brain of rats. For more complete metabolite/metabolite data on 5-hydroxymethyl-2-furfural (a total of 8 metabolites), please visit the HSDB record page. Known metabolites of 5-hydroxymethylfurfural include 5-sulfonylmethylfurfural.

Interactions
Our previous study reported that co-administration of honey after oral administration of glycyrrhizic acid (GZ) to rabbits significantly increased serum glycyrrhetinic acid (GA) levels. Honey comprises sucrose, glucose, fructose, and 5-hydroxymethylfurfural (HMF). To identify the pathogenic components in honey affecting the pharmacokinetics of GZ, we used a crossover design, administering GZ (150 mg/kg) to rabbits, along with glucose (5 g/rabbit), fructose (5 g/rabbit), and HMF (1 mg/kg). Serum concentrations of GZ and GA, as well as fecal concentrations of GA and 3-dehydroglycyrrhetinic acid (3-dehydroGA), were determined using high-performance liquid chromatography (HPLC). Pharmacokinetic parameters were calculated using a non-compartmental model, and statistical comparisons were performed using analysis of variance. Our results showed that co-administration with HMF significantly increased the area under the curve (AUC) of GA by 29%, while co-administration with glucose or fructose had no significant effect on the pharmacokinetics of GZ and GA. An in vitro study, using fecal incubation to incubate glucose oxidase (GZ) and glucose oxidase (GA), showed that high-molecular-weight aldehydes (HMF) significantly inhibited the oxidation of GA to 3-dehydroGA, which may explain the enhanced GA absorption in vivo. This led to the conclusion that HMF is a pathogenic component in honey affecting the first-pass metabolism and pharmacokinetics of GZ in vivo. Chemical analysis of several brands of peritoneal dialysis fluid (PD fluid) revealed the presence of 2-furfural, 5-HMF (5-hydroxymethylfurfural), acetaldehyde, formaldehyde, glyoxal, and methylglyoxal. This study aimed to investigate whether in vitro side effects caused by glucose degradation products (mainly formed during heat sterilization) are related to recently discovered aldehyde compounds. We added different concentrations of aldehyde compounds to cell culture media or sterile filtered peritoneal dialysis fluid. Indicators for determining in vitro side effects included growth inhibition of cultured mouse fibroblasts and stimulation of superoxide radical release from human peritoneal cells. The results indicated that the presence of 2-furfural, 5-hydroxymethylfurfural (5-HMF), acetaldehyde, formaldehyde, glyoxal, or methylglyoxal in heat-sterilized peritoneal dialysis fluid was likely not a direct cause of the in vitro side effects. To achieve the same level of cell growth inhibition as in heat-sterilized peritoneal dialysis fluid, the concentrations of 2-furfural, glyoxal, and 5-HMF would need to be 50 to 350 times higher than those in the peritoneal dialysis fluid. The concentrations of acetaldehyde, formaldehyde, and methylglyoxal observed in heat-sterilized peritoneal dialysis fluid were closer to cytotoxic concentrations, but still 3 to 7 times lower than cytotoxic concentrations. Since these aldehydes did not cause in vitro toxicity at the tested concentrations, the toxicity found in the peritoneal dialysis fluid is likely due to another unidentified glucose degradation product. However, these aldehydes could still potentially have adverse effects on patients undergoing peritoneal dialysis. The effects of water activity (aw 0.98, 0.84, and 0.60) and reaction temperature (100, 120, 140, and 160 °C) on the mutagenic activity of the Maillard reaction products in heated ribose-lysine and glucose-lysine model systems were investigated. In the ribose-lysine system heated to 100 °C, the mutagenic activity of the mixture increased with decreasing water activity. Conversely, no dependence of mutagenic activity on water activity was observed in the glucose-lysine system. At higher temperatures, antimicrobial activity was observed in the browned mixtures of both systems, which interfered with bacterial mutagenicity assays. Under all test conditions, the ribose-lysine system exhibited the highest reactivity and produced the highest levels of mutagens. Furthermore, the antimicrobial interference was more easily detected in this system. The absorption spectra of the browned reaction mixtures in the 200–460 nm range and the accumulation of furfural were analyzed in the model systems used. The results showed a correlation between reaction temperature, absorbance near 420 nm and 280 nm, mutagenic activity of the mixture, and furfural content within a temperature range of 120–140 °C. Changes in furfural content may be related to changes in the mutagenicity of the browning mixture.
Cooked dietary casein at 180 °C promoted the growth of aberrant crypt foci in rat colon cancer induced by azomethane. We hypothesized that this promotion was due to a solvent-extractable product, such as 5-hydroxymethyl-2-furfural (HMF) with pro-tumorigenic activity or carcinogenic heterocyclic aromatic amines (HAA). To verify this hypothesis, we extracted the cooked casein with solvent and water. We then performed the following experiments on the extract: 1) determined the contents of HMF and HAA by high-performance liquid chromatography; 2) determined its mutagenicity against frameshift-sensitive strains of Salmonella Typhimurium; and 3) fed azomethane-induced rats for 100 days to detect its promoting effect on aberrant crypt foci. Data shows that: 1) No HMF or HAA was detected in cooked casein; 2) No mutagenicity was detected in the TA98 strain regardless of whether metabolic activation was performed; 3) The promoting effect was not related to the extract, but to the cooked casein residue...
For more complete data on interactions of 5-hydroxymethyl-2-furfural (6 in total), please visit the HSDB record page.

[1]. Biomass conversion inhibitors furfural and 5-hydroxymethylfurfural induce formation of messenger RNP granules and attenuate translation activity in Saccharomyces cerevisiae. Appl Environ Microbiol. 2013 Mar;79(5):1661-7.

Drug Warnings
When medical fluids contain glucose, the heat applied during sterilization can cause glucose degradation. Glucose degradation products (GDPs) can trigger bioincompatibilities in peritoneal dialysis patients. The degree of degradation depends on various factors, such as heating time, temperature, pH, glucose concentration, and catalysts. This study investigated the effects of pH and concentration on the amount of glucose degradation products generated, aiming to determine how to reduce GDP formation. Glucose solutions (1%–60% glucose; pH 1–8) were heat-sterilized at 121°C. Ultraviolet (UV) absorption, aldehydes, pH, and intracellular growth inhibition (ICG) were used as degradation indicators. The results showed that the degree of glucose degradation was lowest at an initial pH (before sterilization) of approximately 3.5 and a higher glucose concentration. At a higher initial pH, a large amount of acidic degradation products were generated during sterilization. Two distinct patterns of UV-absorbing degradation product formation were observed: one primarily producing 5-hydroxymethyl-2-furfural (5-HMF) at pH below 3.5; the other primarily producing degradation products with absorption at 228 nm at pH above 3.5. The concentration of 3-deoxyglucose ketone (3-DG) and the portion of 228 nm UV absorption not induced by 5-HMF were correlated with in vitro biocompatibility (measured by ICG); absorbance at 5-HMF or 284 nm was not correlated with biocompatibility. To minimize the formation of biocompatible degradation products (GDP) during heat sterilization of peritoneal dialysis fluid, the pH should be maintained around 3.2, along with a high glucose concentration. 5-HMF and 284 nm UV absorbance are not reliable indicators of quality. The portion of 3-DG and degradation products other than 5-HMF at 228 nm appears to be a reliable indicator of biocompatibility. The content of 5-hydroxymethylfurfural (I), a degradation product, in USP glucose injection was determined by ultraviolet spectrophotometry. The content of I in freshly prepared 50% glucose solution was 0.10 μg/mL. Within 24 hours of preparation, the content was 0.72 μg/mL. After storage at 70°F (21°C) for 4 months, the content of I in 50% glucose injection was 5.80 μg/mL. Data for 10% fructose injection were also reported. The conclusion is that a limit standard for the content of I in commercially available solutions can be established. It is recommended that a method for the quantitative determination of this impurity be added to the quality control testing of glucose injection.

C6H6O3

126.11

126.031

C, 57.14; H, 4.80; O, 38.06

67-47-0

5-Hydroxymethylfurfural-13C6;1219193-98-2

237332

Light yellow to light brown solid powder

1.3±0.1 g/cm3

291.5±30.0 °C at 760 mmHg

28-34 °C(lit.)

79.4±0.0 °C

0.0±0.6 mmHg at 25°C

1.563

-0.45

1

3

2

9

103

0

O1C(C([H])=O)=C([H])C([H])=C1C([H])([H])O[H]

NOEGNKMFWQHSLB-UHFFFAOYSA-N

InChI=1S/C6H6O3/c7-3-5-1-2-6(4-8)9-5/h1-3,8H,4H2

5-(hydroxymethyl)furan-2-carbaldehyde

NSC-40738; BAX-555; 5-HMF; AES-103; NSC40738; BAX555; 5HMF; AES103; NSC 40738; BAX 555; 5 HMF; AES 103;5-HMF-AesRx; 5-hydroxymethyl furfural

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~25 mg/mL ( ~198.23 mM ）

Solubility in Formulation 1: ≥ 2.5 mg/mL (19.82 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (19.82 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (19.82 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 10% DMSO+40% PEG300+5% Tween-80+45% Saline: ≥ 2.5 mg/mL (19.82 mM)

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 (Please use freshly prepared in vivo formulations for optimal results.)