Reactive Metabolites in the Biotransformation of Molecules Containing a Furan Ring

These results suggest the involvement of a reactive metabolite in the in vivo toxicity of 2-methylfuran

Lisa A. Peterson

2012

Scholarcy highlights

  • Furan-containing compounds are abundant in food, synthetic and herbal medicines, industrial processes and the environment. Many but not all of these compounds are toxic, causing concerns when human exposure is likely
  • Similar observations were reported when2-methylfuran was incubated with either rat liver or lung microsomes. These results suggest the involvement of a reactive metabolite in the in vivo toxicity of 2-methylfuran
  • The absence of any detectable metabolites in the absence of trapping agents indicates that the enedial intermediate 46 or possible epoxide precursor is very reactive with protein nucleophiles
  • The target organ toxicity exhibited by this group of compounds is often driven by tissue-specific expression of the P450 enzymes responsible for the oxidation of the furan ring
  • Furosemide is relatively non-toxic since its major route of metabolism is glucuronidation, not furan ring oxidation
  • GSH and cysteine blocked 80% and 95% of the protein binding whereas N-acetylcysteine or lysine were only able to block 40–50% of the binding
  • Rapid detoxification of the reactive intermediate results in a less toxic compound. This explains why prasozin is a safe drug despite the fact that furan ring oxidation is a major pathway of metabolism; rapid reduction of the α,β-unsaturated system of the intermediate results in an nontoxic metabolite
  • The less reactive migrate beyond the site of formation and alkylate targets in other subcellular locations

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