5-(Hydroxymethyl)furfural (HMF) arises from acid-catalyzed thermal degradation of hexoses during cooking. There are reports which indicate that HMF can be converted in vitro to a strong mutagen by sulfation of the alcohol functionality and reports that HMF may initiate and promote colonic aberrant crypt foci in rats. Based primarily on these two observations, the NTP has initiated toxicology studies on HMF. As part of this study we have conducted studies of 14C-HMF metabolism and disposition in mice and rats. The emphasis of these studies was to determine if any evidence could be found for in vivo formation of the proposed mutagenic sulfate conjugate. The disposition studies indicate that HMF is rapidly absorbed with no accumulation in tissues. The majority of the radioactivity is eliminated in urine in both mice and rats. Three major urinary metabolites have been isolated and identified. None of the metabolites were the proposed sulfate conjugate and none of them require the intermediacy of the proposed reactive sulfate conjugate. As another measure of reactive intermediates formed from HMF, the amount of unextractable radioactivity associated with protein was determined in selected tissues (protein covalent binding). In general, the amount of unextractable radioactivity was a few tenths of a nmol of HMF equivalents/mg protein. Thus, there is some evidence that reactive intermediates are formed from metabolism of HMF, but at a relatively low rate. o-, m-, and p-Nitrotoluenes are used in the production of dyes, rubber, and agricultural chemicals. Toxicology studies of these chemicals have clearly shown that in F344 rats o-nitrotoluene is the most toxic isomer. All three nitrotoluenes are initially metabolized to the corresponding nitrobenzyl alcohols followed either by further oxidation, or conjugation with small polar endogenous entities such as glucuronic acid or sulfate. An unexplored pathway possibly responsible for the toxicity of o-nitrotoluene is an intramolecular reaction between the o-nitro group and the benzylic carbon bearing a leaving group such as sulfate to give either increased alkylating ability or a reactive metabolite. o- and p-nitrobenzyl p-toluenesulfonates, model compounds for the corresponding sulfates, were prepared and hydrolyzed in CH3CN-H2O. There was little difference in rate of hydrolysis of the two isomers indicating that the difference in toxicity is probably not due to a difference in alkylating ability of a similar metabolite in vivo. p-Toluenesulfonic acid and p-nitrobenzyl alcohol were obtained from p-nitrobenzyl tosylate, as expected. However, hydrolysis of o-nitrobenzyl tosylate gave not only p-toluenesulfonic acid and o-nitrobenzyl alcohol, but also a third product identified as o-nitrosobenzaldehyde. Studies are ongoing to explore biological significance of this observation.
Showing the most recent 10 out of 30 publications
