Hydroxymethylfurfural

Structural formula
General
Surname	Hydroxymethylfurfural
other names	HMF 5- (hydroxymethyl) -2-furaldehyde 5- (hydroxymethyl) -furfurol (hist.) 5-oxymethylfurfurol
Molecular formula	C 6 H 6 O 3
Brief description	white solid
External identifiers / databases
CAS number 67-47-0 EC number 200-654-9 ECHA InfoCard 100,000,595 PubChem 237332 ChemSpider 207215 DrugBank DB12298 Wikidata Q414606
properties
Molar mass	126.11 g mol −1
Physical state	firmly
density	1.21 g cm −3
Melting point	32-35 ° C
boiling point	114 ° C (1.3 h Pa )
safety instructions
GHS labeling of hazardous substances Caution H and P phrases H: 315-319 P: 302 + 352-305 + 351 + 338
Toxicological data	2500 mg kg −1 ( LD 50 ,  rat ,  oral )
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Hydroxymethylfurfural , HMF or 5- (hydroxymethyl) furfural , also 5-oxymethylfurfural , is an aldehyde and furan compound that is formed during the thermal decomposition of sugar or carbohydrates . HMF can be detected in many heat treated foods including milk, fruit juice, alcoholic beverages, honey, etc. Current studies examine the detection of HMF in cigarettes . HMF can be used for modification in the manufacture of plastics. Hexoses, especially fructose , form the HMF through multiple (acid-catalyzed) dehydration.

history

This organic compound 1895 was first described by G. Düll by the dehydration of fructose or sucrose with oxalic acid produced and independently by J. Kiermeyer. Furthermore, the French chemist Louis Maillard observed in 1912 as part of his research on non-enzymatic reactions of glucose and lysine its formation in the Maillard reaction named after him .

Occurrence

HMF in honey

A small amount of HMF in honey is an indicator of its freshness and naturalness. A high HMF value indicates prolonged heating or storage. When honey is heated, fructose turns into HMF. The HMF content in freshly extracted honey is very low and increases by approx. 2-3 mg / kg per year when stored correctly, depending on the pH value and storage temperature. Storage at room temperature (21 ° C) can increase the HMF content to 20 mg / kg in one year. The EU has set a maximum HMF limit value of 40 mg / kg for honey produced under European conditions. Some national beekeeping associations require even lower values, e.g. For example, the German Beekeeping Association allows a maximum of 15 mg / kg for its “Real German Honey” seal of approval.

HMF in honey is mostly detected using high-performance liquid chromatography or the so-called Winkler method . A rapid test for determining HMF has been available from Merck KGaA since 2009 . In the test called “Reflectoquant® HMF”, a small amount of honey is diluted in a ratio of 1: 4 with distilled water , a test strip is dipped into the sample and then measured in a RQflex reflectometer .

Table 1: 5-HMF contents of various foods in mg / kg with sufficiently large measurements

Food	Content in mg / kg (mean value)
honey	9.1
Apple juice	7.4
Grape juice	6.3
Plum jam	410.9
granola bar	36.3
Dried plums	350.8
Beverage powder for coffee	286.1
Mixed rye bread	44.5
Almond, sugar-coated	155.5
Drink made from prunes	1022.1

Manufacture and synthesis

The formation of hydroxymethylfurfural was observed , among other things, during the caramelization of hexoses (e.g. fructose, maltose, glucose). The mechanism of formation corresponds to the scheme leading to furfural in pentoses .

Polymeric sugars such as starch or cellulose also show this reaction. It is known that hexoses can transform into one another through the Lobry-de-Bruyn-Alberda-van-Ekenstein rearrangement . When roasting of chicory roots for the production of coffee substitute is inulin partially converted to hydroxymethylfurfural, which provides for the coffee-like aroma.

In a one-step synthesis, cellulose in the presence of coupled copper (II) chloride / chromium (II) chloride catalysts in the ionic liquid 1-ethyl-3-methylimidazolium chloride as a solvent can be converted into 5-hydroxymethylfurfural (HMF ) are implemented. Under these conditions, the synthesis is about ten times faster than with conventional acid-catalyzed hydrolysis.

Maillard reaction

The Maillard reaction is a chemical reaction between amino acids and reducing sugars that gives browned foods their distinctive taste. The reaction is a form of non-enzymatic browning that typically proceeds rapidly from about 140 to 165 ° C (280 to 330 ° F). At higher temperatures, caramelization (browning of sugar, a distinctive process) and then pyrolysis (final breakdown, which leads to combustion) become more pronounced. One of the end products of the Maillard reaction is 5-hydroxymethylfurfural (5-HMF).

use

5-hydroxymethylfurfural in surgery

Preoperative micronutrient supplements in fast-track surgery programs have been shown to reduce complications, shorten regeneration, and therefore lower costs. The metabolic effects of a combination of α-ketoglutaric acid (AKG) and 5-hydroxymethylfurfural (5-HMF) had an impact on the improvement of performance and the reduction of oxidative stress in lung surgery. Oral supplementation with a combination of α-ketoglutaric acid and 5-HMF can therefore be a further step in a multimodal approach to fast-track surgery programs.

Physiological importance

Possible carcinogenicity

The American National Institute of Environmental Health Sciences gives HMF a high risk that it could be carcinogenic. The reason for this is that other members of this group of compounds show carcinogenic properties. Investigations into the harmfulness of HMF itself, however, have only been carried out to a limited extent.

In studies of various substances with regard to cancer-preventing properties, no such effect could be demonstrated for 5-HMF.

The possible misinterpretation of the carcinogenic property is said to be based on the fact that 5-HMF has only been isolated as a pure substance (> 99%) for a few years. Purest 5-HMF is a colorless powder.

Safety and toxicity

Numerous but diverging studies have been carried out with regard to a possible genotoxic or carcinogenic potential of HMF. Differences in the results can be attributed to different concentrations of HMF used in studies, some of which were extremely high and far removed from the real conditions. Based on this, however, a threshold value of 540 μg / person / day was recommended by the EFSA in 2005, as also stated in the Capuano review. This value is unrealistic, as the estimated HMF intake is 4-30 mg / person / day and can sometimes be up to 350 mg, which in 2011 the German institution for risk assessment, the BfR, came to the following assessment: "5-HMF- According to the current state of scientific knowledge, contents in food are not a health problem ". 5-HMF is also found in high amounts in certain foods and a. in dried fruits 25-2900 mg / kg, caramel products 110-9500 mg / kg or coffee (instant) 400-4100 mg / kg. A very extensive and detailed study of the carcinogenic activity of HMF is described in the NTP report, where it concludes that there is no evidence of carcinogenic activity of 5-HMF in rats under the conditions of these 26-year gavage studies gave (188-375 mg / kg). From this, the BfR concluded that the highest dose derived from animal experiments was between 80 and 100 mg / kg body weight without adverse effects. With an average body weight of 70 kg, this means 5600-7000 mg.

Pharmacokinetics and metabolism

Earlier pharmacokinetic studies were reviewed by Ulbricht and Czok who administered a dose of 100 mg HMF / kg body weight to rats and mice orally or intravenously. Orally administered HMF quickly disappeared from the digestive tract and only trace amounts were detected in blood plasma and urine . This suggests that HMF is rapidly metabolized . After a short time, intravenously injected HMF could no longer be detected in the blood plasma, while only small amounts were detected in the urine and bile . Similar observations were made by Germond. When single oral gavage doses of 5 HMF at 0.08 to 330 mg / kg were administered orally or intravenously, less than 1% of the radioactivity was retained in the body cavity organs and stool. 85% of the radioactivity was eliminated after 8 hours and 95-100% of the radioactivity after 24 hours. 5-Hydroxymethyl-2-furoic acid (HMFA) and N- (5-hydroxymethyl-2-furoyl) glycine were identified as metabolites by NMR and MS . Jellum found in humans that approximately 50% was excreted in the urine as HMFA and furan-2,5-dicarboxylic acid (FDCA) after receiving parenteral HMF with fructose solutions. No unchanged HMF and no glycine conjugates were found in the urine. Godfrey administered HMF orally to mice and rats at doses of 5-500 mg / kg. 60-80% of the administered doses were excreted in the urine within 48 hours. HMFA, FDCA and N- (5-hydroxymethyl-2-furoyl) glycine have been identified as metabolites. Recent pharmacokinetic studies were carried out by Monien. The authors confirmed that HMF is excreted quickly and can no longer be detected in the urine after a short time. In a study of 6 healthy human volunteers, Prior identified 5-hydroxymethyl-2-furoic acid, 5-carboxylic acid-2-furoyl-glycine, N-5-hydroxymethyl-2-furoyl-glycine and 5-carboxylic acid-3-furoyl-aminomethane as Metabolites by HPLC-MS / MS after consumption of 3944 μmol (497 mg) or 486 μmol (61.2 mg) 5-HMF, which are contained in plum juice or dried plums. The estimated total recovery of metabolites was 46.2% and 14.2%, respectively, of the 5-HMF dose during the first 6 hours after consumption. 5-Sulfomethylfurfural (5-SMF), possibly formed by sulfoconjugation, which has been shown / determined to be mutagenic and carcinogenic, was not observed as a metabolite in the above reports with the exception of a recent study by Monien. The authors showed that SMF is formed in HMF-treated mice. LC-MS / MS was used for the analysis. However, SMF has not been found as a metabolite in humans.

function

General mechanism of 5-hydroxymethylfurfural

The main task of 5-HMF is to covalently eliminate ammonia / amines . It reacts with reactive nitrogen species (RNA), such as peroxynitrite , and binds free radicals in its stable resonance system. 5-HMF effectively increases special singlet oxygen transport, satiety, uptake and energy production in the cells. It removes the nitrogen released by the breakdown of amino acids (balancing the body's own nitrogen chemistry and avoiding nitrogen overload). In addition, 5-HMF converts the peroxide production in the inner mitochondrial membrane in the vicinity of the ubiquinone complex into H ₂ O, CO ₂ and the oxidative form succinate . Furthermore, 5-HMF is a very effective, non-enzymatically controlled detoxifying substance for ammonia, which forms azomethine derivatives and is removed directly by urea (e.g. transport of ammonia from the brain).

Mode of Action - intracellular

Four types of free radicals were selected to assess the trapping performance of 5-HMF, including the nitrogen-derived residue DPPH, oxygen-derived hydroxyl and superoxide anion residues, and carbon-derived alkyl residues . 5-HMF had the strongest scavenging activity on the hydroxyl residue at IC50 22.8 μM, compared to the relatively weak alkyl residue at IC50 45.0 μM. 5-HMF showed a significant potency (p <0.05) in trapping hydroxyl radicals in various concentrations, with interrogation proportions of 92% (100 μM), 62% (25 μM), 30% (10 μM) and 7% (1 μM). The IC50 value of 5-HMF was calculated to be 22.8 μM. With regard to the structure of 5-HMF, it contains some interesting functional reactive groups such as double bonds , an aldehyde oxygen atom and another oxygen present in the furan ring, which can easily attract electrons ; in addition, a hydroxyl group can form a singlet oxygen even after the release of a hydrogen ion . These traits should be the main factors behind its antioxidant activity by scavenging excessively producing free radicals in the body and reducing the activity of the oxidizing enzyme (MPO) or increasing the ability of the antioxidant enzymes glutathione (GSH) and superoxide dismutase (SOD) at the gene level. The following properties of 5-HMF have been systematically evaluated: its antioxidant activities; Membrane protein oxidation; oxidative enzyme myeloperoxidase (MPO) inhibition; as well as expressions of selenium containing antioxidant enzymes glutathione (GSH) and superoxide dismutase (SOD) at the gene level. The antioxidant activity of 5-HMF is caused by direct scavenging of cellular ROS and therefore 5-HMF may be developed as a potent antioxidant candidate for inhibiting cellular ROS formation. Recent results confirm the inhibitory effect of 5 HMF on the nitration of tyrosines by peroxynitrite .

Mode of Action - intra- and extracellular

Due to the structure of 5-HMF, it is not only a particularly stable pseudo-aroma, but also has a fully conjugated resonance system due to its carbonyl group . So 5-HMF can keep radical electrons (e.g. peroxynitrite ) stable in its extensive resonance system, which forms long-lived radicals . Another positive effect is the elimination of ONOO- ( peroxynitrite ), a strong oxidizing and deaminating agent for nucleotides, and of OH * radicals (after breakdown of peroxynitrite ), which destroys the membranes of healthy cells. 5-HMF has been identified as a newly discovered drug that induces quinone reductase (QR). This is a well-known phase II detox enzyme.

Comparison of 5-HMF vs. Vitamins

Antioxidants like vitamins C and E react with all free radicals, i. H. also in situ "essential" radicals (immune defense), which leads to many dysfunction. 5-HMF mainly eliminates highly reactive types of nitrogen (RNS) (e.g. peroxides ), but not the "essentials". In their function of removing free radicals, they turn to highly potential substances (e.g. vitamin C radical). These substances can also cause uncontrolled functional disorders (e.g. NOS dysfunction).

literature

1. ↑ ^{a b c d} data sheet Hydroxymethylfurfural at AlfaAesar, accessed on March 14, 2010 ( PDF )(JavaScript required) .
2. ↑ ^{a b c} Data sheet 5- (Hydroxymethyl) -furan-2-carbaldehyd (PDF) from Merck , accessed on April 4, 2011.
3. ↑ G. Düll: On the effect of oxalic acid on inulin . In: Chemiker-Zeitung . tape 19 , no. 116 , 1895, pp. 216-217 .
4. ↑ Jaroslaw Lewkowski: Synthesis, Chemistry and Applications of 5-Hydroxymethyl-furfural and Its Derivatives. In: ChemInform. 34, 2003, doi : 10.1002 / chin.200302269 .
5. ↑ ^{a b} Maillard et al .: Action des acid amines sur les sucres; formation de melanoidines par voie méthodique [Action of amino acids on sugars. Formation of melanoidins in a methodical way]. Comptes Rendus (in French). 154: 66-68.
6. ↑ Catherine Billaud, Jean Adrian: Louis ‐ Camille Maillard, 1878–1936 . In: Food Reviews International . tape 19 , no. 4 , p. 345–374 , doi : 10.1081 / fri-120025480 ( tandfonline.com [accessed May 22, 2017]).
7. ↑ DIN 10751-1: 2010-08: Examination of honey - Determination of the content of hydroxymethylfurfural - Part 1: Photometric method according to Winkler .
8. ↑ ^{a b c} Opinion No. 030/2011: According to current scientific knowledge, 5-HMF contents in foods are not a health problem. BfR, May 15, 2011, accessed on October 30, 2019 . 
9. ↑ Ben-Erik van Wyck: Food Plants of the World Timber Press, 2006, ISBN 0-88192-743-0 . P. 134.
10. ^ Y. Su, HM Brown, X. Huang, X. Zhou, JE Amonette, ZC Zhang: Single-step conversion of cellulose to 5-hydroxymethylfurfural (HMF), a versatile platform chemical . In: Appl. Catalysis . A 361, 2009, pp. 117-122. doi : 10.1016 / j.apcata.2009.04.002 .
11. ↑ Summary in: Chem. Ing. Techn. 81, 2009, p. 679.
12. ^ Matzi et al .: The impact of preoperative micronutrient supplementation in lung surgery. A prospective randomized trial of oral supplementation of combined a-ketoglutaric acid and 5-hydroxymethylfurfural, Eur J CardThorac Surg, 32 (2007): 776-782.
13. ↑ H. Xiao, KL Parkin: Isolation and identification of potential cancer chemopreventive agents from methanolic extracts of green onion (Allium cepa) . In: Phytochemistry . 68, No. 7, 2007, pp. 1059-1067.
14. ↑ H. Xiao, KL Parkin: Induction of phase II enzyme activity by various selenium compounds . In: Nutrition and Cancer . 55. No. 2, 2006, pp. 210-223. doi : 10.1207 / s15327914nc5502_13 .
15. ↑ Capuano, Fogliano et al .: Acrylamide and 5-Hydroxymethylfurfural (HMF): A review on metabolism, toxicity, occurrence in food and mitigation strategies, LWT - Food Science and Technology 44, (2011), 793-810.
16. ↑ Flavoring Group Evaluation 66 (FGE.66) 1: Consideration of furfuryl alcohol and related flavoring substances evaluated by JECFA (55th meeting) structurally related to Furfuryl and furan derivatives with and without additional side chain substituents and heteroatoms evaluated by EFSA in FGE.13 (2005) (EFSA-Q-2008-032R), The EFSA Journal (2009) ON-752, 1-39.
17. ↑ NTP technical report on the toxicology and carcinogenesis studies of 5-HMF (CAS NO. 67-47-0) in F344 / N rats and B6C3F1 mice (Gavage studies), National institutes of Health public health service US Department of health and human services (2008)
18. ↑ Ulbricht et al .: A review of 5-hydroxymethylfurfural (HMF) in parenteral solutions, Fundamental Applied Toxicology, 1984: 4 (5); 843-853.
19. ↑ Czok: Tolerance of 5-hydroxymethylfurfural (HMF). 2nd communication: pharmacologic effects, Z. Ernährwiss, 1970: 10 (2), 103-110.
20. ↑ Germond et al .: Rapid and complete urinary elimination of [14C] -5-hydroxymethyl-2-furaldehyde administered orally or intravenously to rats. Toxicol Environ Health, 1987; 22: 79-89.
21. ↑ Jellum et al .: Presence of furan derivatives in patients receiving fructose-containing solutions intravenously, Clinica Chimica Acta, 1973: 47 (2); 191-201.
22. ↑ Godfrey et al .: Distribution and metabolism of 5-hydroxymethyl furfural in male F344 rats and B6C3F1 mice after oral administration, Journal of Toxicology and Environmental Health, 1999: 57; 199-210.
23. ↑ ^{a b c} Monien et al .: Conversion of the Common Food Constituent 5-Hydroxymethylfurfural into a Mutagenic and Carcinogenic Sulfuric Acid Ester in the Mouse in Vivo, Chem. Res. Toxicol., 2009, 22 (6), 1123-1128.
24. ↑ ^{a b} Prior et al .: Identification and Urinary Excretion of Metabolites of 5- (Hydroxymethyl) -2-furfural in Human Subjects following Consumption of Dried Plums or Dried Plum Juice, J Agric Food Chem, 2006; 54 (10): 3744-9.
25. ↑ Surh et al .: 5-Sulfooxymethylfurfural as a possible ultimate mutagenic and carcinogenic metabolite of the Maillard reaction product, 5-hydroxymethylfurfural, Carcinogenesis, 1994, 15 (10), pp. 2375-2377.
26. ↑ Blomqvist et al .: Glutamine and α -Ketoglutarate Prevent the Decrease in Muscle Free Glutamine Concentration and Influence Protein Synthesis after Total Hip Replacement, Metabolism, Vol 44, No 9 (September), 1995: pp. 1215-1222.
27. ↑ Pfliger: Establishing and measuring the direct and indirect antioxidative effects of AKG, 5HMF and vitamin C in the presence of peroxonitrate, MTUniversity Graz, 2009, 99 Bl, signature: II 723159.
28. ↑ Wagner et al .: The potential antimutagenic and antioxidant effects of Maillard reaction products used as “natural antibrowning” agents, Mol Nutr Food Res., 2007 Apr .; 51 (4): 496-50.