HYDROXYMETHYLFURFURAL (HMF) AND RELATED COMPOUNDS in .NET framework

Generator Code 128 Code Set B in .NET framework HYDROXYMETHYLFURFURAL (HMF) AND RELATED COMPOUNDS
HYDROXYMETHYLFURFURAL (HMF) AND RELATED COMPOUNDS
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pathway II
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CH2OH
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COOH CH OH 2
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CO-SH-CoA CH OH 2 Gly O OH CH2OH
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COOH CH2OH CHO O
(SMF)
(HMFAG)
CH2----OSO3H
(HMFG)
O NH
O OH
(HFA)
COOH O
pathway IV CH2OH O
(CAFG)
NH O
COOH pathway I
COOH
COOH
(KG)
COOH pathway III
O (CAFAM)
Scheme of biotransformation routes for HMF.
estimated for HMFA (36.9%), HMFG (3.4%), CAFG (4.2%), and CAFAM (1.8%). The ratio of HMFA/HMFG excreted in the urine was 10.7 in subjects that consumed dried plum juice and 5.8 in subjects that ate dried plums. These results suggest that increased HMF intake reduces the formation of the glycine conjugate, as reported by Godfrey et al. (167) and Germond et al. (168). HMFA was also rapidly detected in plasma after 30 min of ingestion and began to decline after 60 min (171). In summary, HMF appears to be rapidly metabolized to glycine conjugates and other metabolites and excreted in the urine. A third possible albeit minor route of biotransformation has been described for rodents and involves the complete oxidation of the furan moiety to CO2 (Fig. 2.5.4, route III). The process requires the opening of the furan ring and formation of reactive intermediates (172). HMF and alpha-ketoglutaric acid can be simultaneously determined in human plasma by their respective derivative hydrazones (173). The formation of labeled CO2 from [14C]-furfural and [14C]-furfuryl alcohol in rodents may occur via decarboxylation of 2-furoic acid and formation of alpha-ketoglutaric acid that could enter into the TCA cycle. In addition to the aforementioned pathways, HMF has been shown to be bioactivated in vitro to SMF, through sulfonation of its allylic hydroxyl functional group, catalyzed by sulfotransferases (SULTs) (Fig. 2.5.4, route IV). In the resulting ester, the sulfate is a good leaving group, thus producing a highly electrophilic allyl carbocation, which could be stabilized by distribution of charges on the furan ring. The resulting ester has been demonstrated to induce genotoxic and mutagenic effects. The subsequent interaction of this reactive intermediate with critical cellular nucleophiles (i.e., DNA, RNA, and proteins) may result in structural damages to these macromolecules, thereby
HEALTH RISK: TOXICOLOGY
causing toxicity and mutagenicity, although its occurrence in vivo has not been con rmed yet. This sulfate conjugate appears to be too unstable to allow intact excretion as such and thus detection in urine. Indeed, when HMF was incubated with 35S-PAPS, a sulfo-group donor, and liver cytosol, an unstable conjugate was formed, which disappeared within 60 min. The timedependent decline in the amount of the reaction product appears to be associated with its hydrolysis in an aqueous environment (161). A recent investigation shows that SMF is not present in human urine (8). The authors postulated that one reason may be that SMF is a short-lived metabolite that can react with proteins and DNA and consequently does not appear in the urine. Furthermore, Pryor et al. incubated human urine samples with a mixture of beta-glucuronidase and sulfatase, which did not signi cantly change the area of HMF metabolic substances (171). Today, there is no evidence that glucuronide or sulfate conjugates of HMF are formed in humans. Therefore, it is concluded that non-sulfur furan derivatives, including HMF, cannot be predicted to be metabolized to potentially toxic compounds (169). 2.5.7.3 Genotoxicity, Mutagenicity, and Clastogenicity Potential
Today, it is not con rmed whether human exposure to HMF represents a potential health risk, although it is known that HMF at high concentrations is cytotoxic, causing irritation to eyes, upper respiratory tract, skin, and mucous membranes. However, the in vitro and in vivo data available raise some concern with respect to genotoxicity. Furthermore, the mechanisms by which HMF exerts its genotoxic and tumorigenic effects remain unclear and hence the potential health risk is still a matter of debate. HMF is a multifunctional molecule containing a furan ring, a carbonyl group, and an allylic hydroxyl group that may undergo formation of Schiff bases with amino groups and Michael addition reactions. These reactive sites on the molecule will in uence the biological activity and fate of HMF in the body. Data from epidemiological studies or case reports on potential association of HMF with cancer risk in humans are not available. To support the genotoxic potential of HMF, certain indications of tumorigenic activities of HMF have, however, been deduced from rodent bioassays. HMF can act as an initiator and also as a promoter, as shown for the induction of colonic aberrant crypt foci (ACF; a pre-neoplastic lesion) as marker for colon cancer in rats treated with orally applied HMF (0 300 mg/kg bw) (160, 174, 175), chromosomal aberrations (164), induction of skin papillomas after topical application of 10 25 mmol HMF to mice (161, 162), or development of lipomatous tumors in kidney in rats treated subcutaneously (200 mg/kg bw) (163). In another study in mice, the increase of skin tumor rates associated with HMF treatment was not statistically signi cant (176). Controversial results have been published on mutagenicity/genotoxicity of HMF in vitro by the traditional Ames Salmonella test (177, 178). Experiments