Detection of Glutathione Conjugates Derived From 4-Ipomeanol Metabolism in Bile of Rats by Liquid Chromatography-Tandem Mass Spectrometry

Alvarez-Diez, Teresa M.; Zheng, Jiang

doi:10.1124/dmd.104.000406

Cited by 27 publications

(31 citation statements)

References 27 publications

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“…Their absence does not mean that they are not formed in vivo. Given their size, they may be preferentially eliminated via the bile as has been observed for the GSH conjugates of structurally related 4-ipomeanol (19). We are investigating whether these compounds and their metabolites are presented in the feces of furan-treated rats.…”

Section: Or N-{4-carboxy-4-[3-s-(n-acetylcysteinyl)-1h-pyrrol-1-yl]-1mentioning

confidence: 99%

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: Or N-{4-carboxy-4-[3-s-(n-acetylcysteinyl)-1h-pyrrol-1-yl]-1mentioning

confidence: 99%

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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“…In addition, the presence of a stable 5; 8∕5 0 ; 8 0 -monofuran would be consistent with previously described mechanisms (13,17) whereas the C-C single bond associated with the peroxide at the 5, 6 (or 5 0 , 6 0 ) position in the cyclohexenyl ring would remain intact despite O-O bond photocleavage (13). In addition, the structures proposed for the precursor molecular ions were guided by mass spectrometry principles (18): (i) direct MS/MS cleavage at double bonds does not occur because of the high energy requirements (19); (ii) MS/MS fragmentation processes generally involve a loss of water from a substituted ethanol group and a loss of CO from an aldehyde; in the case of an aldehyde conjugated to the pyridinium ring, no loss of CO is observed; (iii) even-mass fragment ions containing the positive charge of the pyridinium group would form via homolytic cleavages at charge remote sites; (iv) oddmass product ion peaks would be radicals due to charge remote radical homolytic cleavages wherein the charge resides on the pyridinium group and a free radical resides at the fragmentation site; (v) homolytic charge remote site reactions would involve hydrogen and/or methyl rearrangements; (vi) oxygens could be added to aldehyde structures to satisfy elemental compositions and peroxides could undergo losses of atomic oxygen; and (vii) the C12-C13 and C14 0 -C15 0 single bonds of A2E would be strengthened by the C11-C12 and C13 0 -C14 0 double bonds, respectively, that are conjugated with double bonds situated in the aromatic ring (20,21). Importantly, the proposed structures of the precursor and product ions of the 8 photocleavage products, were also supported by exact-mass measurements performed utilizing ESI-Fourier transform-ion cyclotron resonance (FT-ICR) MS and MS/MS.…”

Section: Characterization Of A2e Photocleavage Products By Tandemmentioning

confidence: 99%

Structural characterization of bisretinoid A2E photocleavage products and implications for age-related macular degeneration

Yanase

Feng

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

128

118

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Fluorescent bisretinoids, such as A2E and all-trans-retinal dimer, form as a by-product of vitamin A cycling in retina and accumulate in retinal pigment epithelial (RPE) cells as lipofuscin pigments. These pigments are implicated in pathological mechanisms involved in several vision-threatening diseases including age-related macular degeneration. Efforts to understand damaging events initiated by these bisretinoids have revealed that photoexcitation of A2E by wavelengths in the visible spectrum leads to singlet oxygen production and photooxidation of A2E. Here we have employed liquid chromatography coupled to electrospray ionization mass spectrometry together with tandem mass spectrometry (MS/MS), to demonstrate that A2E also undergoes photooxidation-induced degradation and we have elucidated the structures of some of the aldehyde-bearing cleavage products. Studies in which A2E was incubated with a singlet oxygen generator yielded results consistent with a mechanism involving bisretinoid photocleavage at sites of singlet molecular oxygen addition. We provide evidence that one of the products released by A2E photodegradation is methylglyoxal, a low molecular weight reactive dicarbonyl with the capacity to form advanced glycation end products. Methylglyoxal is already known to be generated by carbohydrate and lipid oxidation; this is the first report of its production via bisretinoid photocleavage. It is significant that AGE-modified proteins are detected in deposits (drusen) that accumulate below RPE cells in vivo; drusen have been linked to age-related macular degeneration pathogenesis. Whereas various processes play a role in drusen formation, these findings are indicative of a contribution from lipofuscin photooxidation in RPE.advanced glycation end products | lipofuscin | photofragmentation | photooxidation | retinal pigment epithelial cells F luorescent bisretinoid pigments are amassed as lipofuscin in retinal pigment epithelial (RPE) cells in association with aging although individuals vary with respect to the extent of accumulation (1). The excessive deposition of these compounds in RPE cells is also considered to lead to retinal degeneration in early onset blinding disorders associated with mutations in the genes encoding ABCA4 (ATP-binding cassette subfamily A member 4) (2, 3), ELOVL4 (4), and BEST-1 (5). Moreover, the deposition of these pigments likely also contributes to the etiology of agerelated macular degeneration (AMD) (6, 7). Whereas these bisretinoids constitute a complex mixture, all appear to originate from reactions of all-trans-retinal and some have been identified, including A2E (Fig. 1) and its isomers (8); A2-dihydropyridinephosphatidylethanolamine (A2-DHP-PE) and A2-dihydropyridine-ethanolamine (A2-DHP-E) (9); and all-trans-retinal dimer, all-trans-retinal dimer-phosphatidylethanolamine (all-transretinal dimer-PE), and all-trans-retinal dimer-ethanolamine (alltrans-retinal dimer-E) (10, 11). Structural features common to all of these pigments are the alternating single and double carbon...

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“…GSH was chosen as the trapping agent since it protects against the majority of cytochrome P450-catalyzed protein binding of [ 14 C]furan (Parmar and Burka, 1993) and will not inhibit cytochrome P450. Trapping reactive metabolites with GSH or other sulfhydryl reagents has been used as a method to estimate the extent of metabolic activation for a number of drugs and environmental compounds (Tang et al, 1999;Smith et al, 2003;Alvarez-Diez and Zheng, 2004;Baer et al, 2005;Gan et al, 2005). In this report, we describe the development of an HPLC-electrochemical (HPLC-EC) detection method for the detec-tion of cis-2-butene-1,4-dial-GSH conjugates and its application to determine the extent of the cytochrome P450-catalyzed oxidation of furan in microsomal preparations.…”

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confidence: 99%

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

Peterson

Cummings

et al. 2005

Drug Metab Dispos

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ABSTRACT:Furan is a liver carcinogen and toxicant. Furan is oxidized to the reactive dialdehyde, cis-2-butene-1,4-dial, by microsomal enzymes. This reactive metabolite readily reacts with glutathione nonenzymatically to form conjugates. A high-performance liquid chromatography-electrochemical method for the detection of cis-2-butene-1,4-dial-glutathione (GSH) conjugates in microsomal preparations was developed to measure the extent of furan metabolism to cis-2-butene-1,4-dial in vitro. Previously unobserved mono-GSH reaction products of cis-2-butene-1,4-dial were detected in addition to the already characterized bis-GSH conjugates. Chemical characterization of these compounds indicated that the ␣-amino group of glutathione had reacted with cis-2-butene-1,4-dial to form a thiol-substituted pyrrole adduct. The analytical method was used to estimate the extent of furan oxidation in rat liver microsomes from untreated or acetone-pretreated F344 rats as well as in human P450 2E1 Supersomes. Our results confirm that cytochrome P450 2E1 can catalyze the oxidation of furan to cis-2-butene-1,4-dial. However, the data are also consistent with the involvement of other P450 enzymes in the oxidation of furan in untreated animals. This assay will be a valuable tool to explore tissue and species differences in rates of furan oxidation.

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Detection of Glutathione Conjugates Derived From 4-Ipomeanol Metabolism in Bile of Rats by Liquid Chromatography-Tandem Mass Spectrometry

Cited by 27 publications

References 27 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

Structural characterization of bisretinoid A2E photocleavage products and implications for age-related macular degeneration

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

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