Toxicity mediated by reactive metabolites of furans.
Furan derivatives occur widely in the environment, and several of these compounds cause necrosis of target cells within certain organs, including the liver, the kidneys, and the lungs. The tissue specificity may vary from compound to compound. For individual compounds, the specificity may be greatly influenced by the species, sex, and age of the test animal and by the prior exposure of the animal to inducers of drug metabolism. Studies in vitro and in vivo indicate that cytochrome P-450 enzymes in the target tissues mediate the formation of highly reactive, electrophilic furan metabolites that bind covalently to tissue macromolecules. Epoxides are suspected, but not proven, to be the proximate or ultimate toxic metabolites of furans. One study suggested that epoxide hydratase might influence the covalent binding of a furan derivative in vitro, but similar investigations with other furans have been negative. Glutathione (GSH) can inhibit the covalent binding of reactive furan metabolites in vitro, presumably by forming less reactive, water-soluble conjugates with the activated furans. GSH-furan conjugate formation can occur nonenzymatically, and a study with 4-ipomeanol indicated that cytosolic enzyme preparations did not enhance the amounts of conjugates produced. It is likely that GSH provides a major mechanism for detoxification of some furans in vivo.
D000818:Animals; D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004851:Epoxide Hydrolases / Q000378:metabolism; D005260:Female; D005663:Furans / Q000378:metabolism* / Q000633:toxicity; D005978:Glutathione / Q000378:metabolism / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice
D005663:Furans; D003577:Cytochrome P-450 Enzyme System; D004851:Epoxide Hydrolases; D005978:Glutathione