Gates L, Lu D, Peterson LA.
University of Minnesota.
Furan is a liver toxicant and carcinogen in rodents. It is classified as a possible human carcinogen, but the human health effects of furan exposure remain unknown. The oxidation of furan by cytochrome P450 enzymes (CYPs) is necessary for furan toxicity. The product of this reaction is the reactive α,β-unsaturated dialdehyde, cis-2-butene-1,4-dial (BDA). To determine if human liver microsomes metabolize furan to BDA, a LC-MS/MS method was developed to detect and quantify BDA by trapping this reactive metabolite with N-acetyl-L-cysteine (NAC) and N-acetyl-L-lysine (NAL). Reaction of NAC and NAL with BDA generates N-acetyl-S-[1-(5-acetylamino-5-carboxypentyl)-1H-pyrrol-3-yl]-L-cysteine (NAC-BDA-NAL). Formation of NAC-BDA-NAL was quantified in 21 different human liver microsomal preparations. The levels of metabolism were comparable to that observed in F344 rat and B6C3F1 mouse liver microsomes, two species known to be sensitive to furan-induced toxicity. Studies with recombinant human liver CYPs indicated that CYP2E1 is the most active human liver furan oxidase. The activity of CYP2E1 as measured by p-nitrophenol hydroxylase activity was correlated to the extent of NAC-BDA-NAL formation in human liver microsomes. The formation of NAC-BDA-NAL was blocked by CYP2E1 inhibitors but not other CYP inhibitors. These results suggest that humans are capable of oxidizing furan to its toxic metabolite, BDA, at comparable rates to species sensitive to furan exposure. Therefore, humans may be susceptible to furan's toxic effects.