GLUTATHIONE TRAPPING TO MEASURE MICROSOMAL OXIDATION OF FURAN TO<i>CIS</i>-2-BUTENE-1,4-DIAL

Peterson, Lisa A.; Cummings, Meredith E.; Vu, Choua C.; Matter, Brock

doi:10.1124/dmd.105.004432

Cited by 77 publications

(86 citation statements)

References 24 publications

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“…We have shown that cis-2-butene-1,4-dial reacts rapidly with GSH to form both mono-and bis-GSH reaction products in microsomes (1 and 2, respectively, Scheme 1) (11,12). Therefore, if cis-2-butene-1,4-dial is formed in vivo, we expected that it would be trapped by GSH.…”

Section: Resultsmentioning

confidence: 99%

“…[ 13 C 4 ] Furan, cis-2-butene-1,4-dial, and the mono-and bis-GSH conjugates of cis-2-butene-1,4-dial were prepared as previously described (11,12,14,16). Furan was distilled before use and its purity was confirmed by NMR.…”

Section: Methodsmentioning

confidence: 99%

“…Urine from individual animals treated with [ 12 C 4 ]-or [ 13 C 4 ]furan were analyzed separately as well as a 1:1 mixture. In some cases, the samples were treated with TCEP prior to MS analysis to reduce any disulfide bonds (12). The resulting data were searched for compounds that were present in the samples from furan-treated rats, absent in the samples from control rats and shifted by four amu in the urine from [ 13 C 4 ]furan-treated treated rats.…”

Section: Lc-ms Analysis Of Urinementioning

confidence: 99%

“…Similarly, these toxic effects are reduced in the presence of cytochrome P-450 inhibitors (5)(6)(7)(8)(9). The initial product of microsomal furan oxidation is cis-2-butene-1,4-dial (Scheme 1) (10)(11)(12). This reactive α,β-unsaturated dialdehyde is likely to be a candidate for the ultimate toxic and carcinogenic properties of furan since it readily reacts with protein and DNA nucleophiles (11,13,14) and is a bacterial mutagen (15).…”

Section: Introductionmentioning

confidence: 99%

“…cis-2-Butene-1,4-dial reacts rapidly with GSH to form mono-and bis-GSH reaction products (1 and 2, respectively, Scheme 1) (10)(11)(12). Therefore, we developed stable isotope mass spectral methods to detect the GSH conjugates of cis-2-butene-1,4-dial and their subsequent metabolites (Scheme 1 and 2) in the urine of furan-treated rats.…”

Section: Introductionmentioning

confidence: 99%

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

Peterson

Cummings

Chan

et al. 2006

Chem. Res. Toxicol.

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The hepatocarcinogen and toxicant, furan, requires metabolic activation to elicit its toxic effects. The available experimental evidence indicate that the overall metabolism of furan is initiated via cytochrome P450 catalyzed oxidation to cis-2-butene-1,4-dial. This α,β-unsaturated dialdehyde reacts in vitro with protein and DNA nucleophiles. To determine if this compound is an in vivo intermediate in the metabolism of furan, rats were treated with either [ 12 C 4 ]furan or [ 13 C 4 ]furan and urine was collected for 24 h. Capillary LC/MS/MS analysis of the urine indicated that one of the metabolites was a mono-glutathione conjugate of cis-2-butene-1,4-dial. These results indicate that glutathione conjugation of the reactive metabolite of furan occurs in vivo. This metabolite may serve as a useful marker for furan exposure and metabolism in risk assessment studies.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Lc-ms Analysis Of Urinementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Peterson

Cummings

Chan

et al. 2006

Chem. Res. Toxicol.

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Role of Reactive Metabolites in Genotoxicity

Kalgutkar

Dalvie

Obach

et al. 2012

Reactive Drug Metabolites

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The Oxidation of Oxygen and Sulfur‐Containing Heterocycles by Cytochrome P450 Enzymes

Podgorski

Keto

Coleman

et al. 2023

Chemistry A European J

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The cytochrome P450 (CYP) superfamily of monooxygenase enzymes play important roles in the metabolism of molecules which contain heterocyclic, aromatic functional groups. Here we study how oxygen‐ and sulfur‐containing heterocyclic groups interact with and are oxidized using the bacterial enzyme CYP199A4. This enzyme oxidized both 4‐(thiophen‐2‐yl)benzoic acid and 4‐(thiophen‐3‐yl)benzoic acid almost exclusively via sulfoxidation. The thiophene oxides produced were activated towards Diels‐Alder dimerization after sulfoxidation, forming dimeric metabolites. Despite X‐ray crystal structures demonstrating that the aromatic carbon atoms of the thiophene ring were located closer to the heme than the sulfur, sulfoxidation was still favoured with 4‐(thiophen‐3‐yl)benzoic acid. These results highlight a preference of this cytochrome P450 enzyme for sulfoxidation over aromatic hydroxylation. Calculations predict a strong preference for homodimerization of the enantiomers of the thiophene oxides and the formation of a single major product, in broad agreement with the experimental data. 4‐(Furan‐2‐yl)benzoic acid was oxidized to 4‐(4′‐hydroxybutanoyl)benzoic acid using a whole‐cell system. This reaction proceeded via a γ‐keto‐α,β‐unsaturated aldehyde species which could be trapped in vitro using semicarbazide to generate a pyridazine species. The combination of the enzyme structures, the biochemical data and theoretical calculations provides detailed insight into the formation of the metabolites formed from these heterocyclic compounds.

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GLUTATHIONE TRAPPING TO MEASURE MICROSOMAL OXIDATION OF FURAN TOCIS-2-BUTENE-1,4-DIAL

Cited by 77 publications

References 24 publications

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

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

Role of Reactive Metabolites in Genotoxicity

The Oxidation of Oxygen and Sulfur‐Containing Heterocycles by Cytochrome P450 Enzymes

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