Conversion of the Common Food Constituent 5-Hydroxymethylfurfural into a Mutagenic and Carcinogenic Sulfuric Acid Ester in the Mouse in Vivo

Abstract

5-Hydroxymethylfurfural (HMF), formed by acid-catalyzed dehydration and in the Maillard reaction from reducing sugars, is found at high levels in numerous foods. It was shown to initiate colon aberrant crypt foci in rats and skin papillomas and hepatocellular adenomas in mice. HMF is inactive in in vitro genotoxicity tests using standard activating systems but is activated to a mutagen by sulfotransferases. The product, 5-sulfoxymethylfurfural (SMF), is a stronger carcinogen than HMF. SMF has not been detected in the biotransfomation experiments conducted on HMF in humans and animals in vivo up to date. Here, we report pharmacokinetic properties of HMF and SMF in FVB/N mice. Sensitive assays for the quantification of HMF and SMF by LC-MS/MS multiple reaction monitoring were devised. SMF, intravenously injected (4.4 micromol/kg body mass), showed first-order elimination kinetics in blood plasma (t(1/2) = 7.9 min). HMF, injected intravenously (793 micromol/kg body mass), demonstrated biphasic kinetics in plasma (t(1/2) = 1.7 and 28 min for the initial and terminal elimination phases, respectively); the volume of distribution of the central compartment corresponded approximately to the total body water. The maximum SMF plasma level was observed at the first sampling time, 2.5 min after HMF administration. On the basis of these kinetic data, it was estimated that between 452 and 551 ppm of the initial HMF dose was converted to SMF and reached the circulation. It is likely that additional SMF reacted with cellular structures at the site of generation and thus is ignored in this balance. Our work supports the hypothesis that HMF-related carcinogenicity may be mediated by its reactive metabolite SMF.

Renal organic anion transporters OAT1 and OAT3 mediate the cellular accumulation of 5-sulfooxymethylfurfural, a reactive, nephrotoxic metabolite of the Maillard product 5-hydroxymethylfurfural

“…However, SMF is chemically reactive, making its detection in biological samples difficult. The half-life time of SMF in aqueous solutions at 37°C amounts to nearly 2 h. Recent studies conducted in our laboratory demonstrate the formation of SMF from HMF in the mouse in vivo [22]. SMF was detected in blood samples of FVB/N mice after intravenous administration of HMF.…”

“…The calibration curves were linear in the range between 500 nM (2 pmol/injection) and 1 nM (4 fmol/injection) SMF (r 2 ≥ 0.993). Details of the method has been published elsewhere [22].…”

5-Hydroxymethyl-2-Furfural (HMF) – Heat-Induced Formation, Occurrence in Food and Biotransformation - a Review

“…Recently, in vivo studies by Monien et al [2009] first proved that SMF is formed in HMF-treated mice. The maximum SMF plasma level was observed at the first sampling time, 2.5 min after HMF administration.…”

Hydroxymethyl furfural in chinese herbal medicines: Its formation, presence, metabolism, bioactivities and implications

“…Apart from HMFA, FDCA and HMFG have also been detected in human urine (Pettersen and Jellum, 1972). In addition, HMF can also be metabolized to sulfooxymethylfurfural (SMF), which has been proven to induce genotoxicity (Monien et al, 2009). …”