The Formation of Substituted 1,N⁶-Etheno-2‘-deoxyadenosine and 1,N²-Etheno-2‘-deoxyguanosine Adducts by cis-2-Butene-1,4-dial, a Reactive Metabolite of Furan

Abstract

Furan is an environmental chemical that induces liver toxicity and tumor formation in rodents, leading to its classification as a probable human carcinogen. cis-2-Butene-1,4-dial, the metabolite considered responsible for furan's toxicological effects, is mutagenic in the Ames assay and reacts with 2'-deoxycytidine (dCyd), 2'-deoxyadenosine (dAdo), and 2'-deoxyguanosine (dGuo) to form previously characterized diastereomeric adducts. The initially formed dCyd adducts are stable to rearrangement, while the dAdo and dGuo adducts are unstable and rearrange to form secondary products. On the basis of UV absorbance, fluorescence, 1H NMR, and mass spectral data, the rearrangement product of the dAdo adduct was identified as the substituted etheno-dAdo adduct, 1''-[3-(2'-deoxy-beta-D-erythropentafuranosyl)-3H-imidazo[2,1-i]purin-8-yl]ethane-2''-al. The NMR characterization of the O-methyloxime derivative of the secondary dGuo adduct, along with mass spectral and UV data on the underivatized adduct, allowed for its structural assignment as the substituted etheno-dGuo compound, 3-(2'-deoxy-beta-D-erythropentafuranosyl)imidazo-7-(ethane-2''-al)[1,2-alpha]purine-9-one. The characterization of the primary and secondary products formed in the reaction of cis-2-butene-1,4-dial with nucleosides is important for understanding the mechanism of furan-induced carcinogenesis. These secondary adducts retain a reactive aldehyde with the potential to form cross-links and are likely to contribute significantly to furan's toxic and carcinogenic effects.

Identification of a cis-2-Butene-1,4-dial-derived Glutathione Conjugate in the Urine of Furan-Treated Rats

“…in the metabolite derived from [ 13 C 4 ]furan (Figure 3). In addition, high resolution mass spectral analysis is consistent with the proposed structure (accurate mass for C 14 The observation of this metabolite in the urine of furan-treated rats indicates that cis-2-butene-1,4-dial is formed and trapped with GSH in vivo. The major reaction product formed between cis-2-butene-1,4-dial and GSH in vitro are the bis-GSH conjugates (11,12).…”

Trapping of cis-2-Butene-1,4-dial to Measure Furan Metabolism in Human Liver Microsomes by Cytochrome P450 Enzymes

“…Aqueous solutions of BDA were prepared from 2,5-diacetoxy-2,5-dihydrofuran as previously described (Byrns et al, 2004). -Lcysteine (NAC-BDA-NAL) was synthesized as reported previously (Lu et al, 2009).…”

“…Its toxicity is reduced by CYP2E1 inhibitors and enhanced by CYP2E1 inducers Kedderis et al, 1993). BDA is genotoxic (Marinari et al, 1984;Peterson et al, 2000;Kellert et al, 2008a) and forms adducts with various cellular nucleophiles such as DNA, protein, and polyamines (Chen et al, 1997;Gingipalli and Dedon, 2001;Byrns et al, 2002Byrns et al, , 2004Lu et al, 2009;Peterson et al, 2011), which is evidence that BDA may be responsible for furan-induced toxicities. Conjugates of BDA have been detected in the urine and bile of furan-treated rats (Peterson et al, 2006(Peterson et al, , 2011Kellert et al, 2008b;Lu et al, 2009;Hamberger et al, 2010;Lu and Peterson, 2010).…”

Hepatobiliary Toxicity of Furan: Identification of Furan Metabolites in Bile of Male F344/N Rats

“…, were prepared as described previously (Chen et al, 1997;Byrns et al, 2004;Peterson et al, 2005). In addition to the bis-GSH conjugates, a further reaction product eluting at 15.6 min was formed when BDA was reacted with 10 equivalents of GSH, and this was identified as L-cysteinylglycine (231Ј)-sulfide with N- [4-carboxy-4-(3-mercapto-1H-…”