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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Intramural Research (Z01)
Project #
1Z01ES021075-15
Application #
6106564
Study Section
Special Emphasis Panel (LPC)
Project Start
Project End
Budget Start
Budget End
Support Year
15
Fiscal Year
1998
Total Cost
Indirect Cost
City
State
Country
United States
Zip Code
Lo, Yi-Ching; Liu, Yuxin; Lin, Yi-Chin et al. (2008) Neuronal effects of 4-t-Butylcatechol: a model for catechol-containing antioxidants. Toxicol Appl Pharmacol 228:247-55
Clayton, Natasha P; Yoshizawa, Katsuhiko; Kissling, Grace E et al. (2007) Immunohistochemical analysis of expressions of hepatic cytochrome P450 in F344 rats following oral treatment with kava extract. Exp Toxicol Pathol 58:223-36
Ferguson, Ling-Jen Chen; Lebetkin, Edward H; Lih, Fred B et al. (2007) 14C-labeled pulegone and metabolites binding to alpha2u-globulin in kidneys of male F-344 rats. J Toxicol Environ Health A 70:1416-23
Chen, L-J; Lebetkin, E H; Sanders, J M et al. (2006) Metabolism and disposition of 2,2',4,4',5-pentabromodiphenyl ether (BDE99) following a single or repeated administration to rats or mice. Xenobiotica 36:515-34
Sanders, J M; Lebetkin, E H; Chen, L-J et al. (2006) Disposition of 2,2',4,4',5,5'-hexabromodiphenyl ether (BDE153) and its interaction with other polybrominated diphenyl ethers (PBDEs) in rodents. Xenobiotica 36:824-37
Garner, C E; Sumner, S C J; Davis, J G et al. (2006) Metabolism and disposition of 1-bromopropane in rats and mice following inhalation or intravenous administration. Toxicol Appl Pharmacol 215:23-36
Chen, Ling-Jen; DeRose, Eugene F; Burka, Leo T (2006) Metabolism of furans in vitro: ipomeanine and 4-ipomeanol. Chem Res Toxicol 19:1320-9
Sanders, J M; Chen, L-J; Lebetkin, E H et al. (2006) Metabolism and disposition of 2,2',4,4'- tetrabromodiphenyl ether following administration of single or multiple doses to rats and mice. Xenobiotica 36:103-17
Mathews, James M; Etheridge, Amy S; Valentine, John L et al. (2005) Pharmacokinetics and disposition of the kavalactone kawain: interaction with kava extract and kavalactones in vivo and in vitro. Drug Metab Dispos 33:1555-63
Irwin, Richard D; Parker, Joel S; Lobenhofer, Edward K et al. (2005) Transcriptional profiling of the left and median liver lobes of male f344/n rats following exposure to acetaminophen. Toxicol Pathol 33:111-7

Showing the most recent 10 out of 30 publications