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

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

doi:10.1021/tx060111x

Cited by 45 publications

(55 citation statements)

References 16 publications

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“…Within 30 min of furan application, several furan-derived metabolites were excreted in bile, including the mono-GSH conjugate of BDA a (m/z 354), which has previously been identified in hepatocyte cultures and urine of rats exposed to furan (Peterson et al, 2006;Kellert et al, 2008b;Lu et al, 2009) and a GSH-BDA-glutamic acid adduct b (m/z 501) (Peterson et al, 2006). In addition, four not previously characterized metabolites c to f were detected (Fig.…”

Section: Identification Of Biliary Furan Metabolitesmentioning

confidence: 71%

“…was obtained by incubation of BDA with equimolar amounts of GSH and L-glutamic acid (Peterson et al, 2006). -1H-pyrrol-3-yl}L-cysteine (g) was prepared by combining BDA with equimolar amounts of N ␣ -acetyl-L-lysine and N-acetyl-L-cysteine as described previously (Chen et al, 1997).…”

Section: Methodsmentioning

confidence: 99%

“…These include a cyclic mono-GSH conjugate, a glutamic acid methanethiol conjugate, a N-acetyllysine conjugate, and a N-acetylcysteine-N-acetyllysine conjugate and its sulfoxide, which were detected in urine of rats exposed to furan (Peterson et al, 2006;Kellert et al, 2008b;Lu et al, 2009). In addition, the mono-GSH conjugate, the N-acetylcysteine-N-acetyllysine conjugate, a N-acetylcysteine-lysine conjugate, and metabolites in which the thiol group of GSH is cross-linked by BDA with an amino group of glutamine, lysine, or N-acetyllysine were found in culture media of primary rat hepatocytes treated with furan in vitro (Lu et al, 2009) GSH and glutamic acid BDA conjugates with N-acetylcysteine were previously identified in in vitro reaction mixtures (Peterson et al, 2006). The objective of this study was to structurally characterize furan metabolites excreted with bile after oral administration of furan to rats to better understand the potential role of reactive furan intermediates in the biliary toxicity of furan.…”

Section: Introductionmentioning

confidence: 99%

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

Hamberger

Kellert²,

Schauer³

et al. 2010

Drug Metab Dispos

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ABSTRACT:Furan, which occurs in a wide variety of heat-treated foods, is a potent hepatotoxicant and liver carcinogen in rodents. In a 2-year bioassay, furan caused hepatocellular adenomas and carcinomas in mice and rats but also high incidences of bile duct tumors in rats. Furan is bioactivated by cytochrome P450 enzymes to cis-2-butene-1,4-dial, an ␣,␤-unsaturated dialdehyde, which readily reacts with tissue nucleophiles. The objective of this study was to structurally characterize furan metabolites excreted with bile to better understand the potential role of reactive furan intermediates in the biliary toxicity of furan. Bile duct-cannulated F344/N rats (n ‫؍‬ 3) were administered a single oral dose of 5 mg/kg b.wt. The main metabolite was a cyclic monoglutathione conjugate of cis-2-butene-1,4-dial, which was previously detected in urine of furan-treated rats. Furthermore, a N-acetylcysteine-N-acetyllysine conjugate, previously observed in rat urine, and a cysteinylglycine-glutathione conjugate were identified as major metabolites. These data suggest that degraded protein adducts are in vivo metabolites of furan, consistent with the hypothesis that cytotoxicity mediated through binding of cis-2-butene-1,4-dial to critical target proteins is likely to play a key role in furan toxicity and carcinogenicity.

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Section: Identification Of Biliary Furan Metabolitesmentioning

confidence: 71%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Hamberger

Kellert²,

Schauer³

et al. 2010

Drug Metab Dispos

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“…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).…”

Section: Food and Drug Administration Exploratory Data On Furan In Fmentioning

confidence: 99%

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

2011

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ABSTRACT: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 (P450) enzymes is necessary for furan toxicity. The product of this reaction is the reactive ␣,␤-unsaturated dialdehyde, cis-2-butene-1,4-dial (BDA). To determine whether human liver microsomes metabolize furan to BDA, a liquid chromatography/tandem mass spectrometry 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 micro-somal preparations. The levels of metabolism were comparable to that observed in F-344 rat and B6C3F1 mouse liver microsomes, two species known to be sensitive to furan-induced toxicity. Studies with recombinant human liver P450s 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 P450 inhibitors. These results suggest that humans are capable of oxidizing furan to its toxic metabolite, BDA, at rates comparable to those of species sensitive to furan exposure. Therefore, humans may be susceptible to furan's toxic effects.

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“…This event leads to an increase in the production of reactive oxygen species (ROS). ROS cause mutations in protein and DNA, lipid peroxidation in membranes, apoptosis, and damage to cellular structures (4,5). The amount of oxygen is very low in the testes due to weak vascularity.…”

Section: Introductionmentioning

confidence: 99%

Furan toxicity on testes and protective role of lycopene in diabetic rats

Kara¹,

Baş²,

Pandır³

2016

J Turkish German Gynecol Assoc

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Material and Methods35 male adult Wistar albino rats weighing 300 to 320 g were obtained from the Experimental Animal Laboratory of Çukurova University. The rats were inserted into special plasObjective: Furan (C 4 H 4 O) is a heat-induced food contaminant that is utilized as an industrial chemical agent. Lycopene is a natural substance that is produced by plants and tomatoes. We aimed to evaluate the toxicity of furan on testes and the protective effect of lycopene in diabetic rats. Material and Methods:Male Wistar albino rats were divided into five groups: Group 1 (control group) received 1 mL/kg corn oil. Group 2 (diabetic control group) received 55 mg/kg STZ and 1 mL/kg corn oil. Group 3 (diabetic lycopene group) received 55 mg/kg STZ and 4 mg/kg lycopene. Group 4 (diabetic furan group) received 55 mg/kg STZ and 40 mg/kg furan. Group 5 (diabetic furan + lycopene group) received 55 mg/kg STZ, 40 mg/kg furan, and 4 mg/kg lycopene. After 28 days, the testes were extirpated in all groups. In the testicular tissue samples, the level of malondialdehyde (MDA) and the activities of catalase (CAT), glutathione peroxidase (GPx), superoxide dismutase (SOD), and reducted glutathione (GST) were studied. Serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone levels were measured. Histopathologic examination was performed by light microscope. Results:The MDA level and the activities of CAT, GPx, SOD, and GST were found to be higher in the furan group than in the control and diabetic control groups (p<0.05). The MDA level and the activities of CAT, GPx, SOD, and GST were significantly lower in the furan + lycopene group than in the furan group (p<0.05). Conclusion:The low blood testosterone level in the rats who received furan suggested the presence of endocrinological defects and cellular degenerative changes. Lycopene may be effective to reverse furan toxicity in diabetic rat testes. (J Turk Ger Gynecol Assoc 2016; 17: 191-6) Keywords: Furan, rat, testis, toxicity, lycopene, diabetes mellitus Received: 23 August, 2016 Accepted: 15 October, 2016 Furan toxicity on testes and protective role of lycopene in diabetic rats Özlem Kara, Hatice Baş, Dilek Pandır Department of Biology, Bozok University School of Arts and Science, Yozgat, Turkey Abstract tic cages and were fed with free access to both water and a standard pellet diet. The study was approved by the Institutional Ethics Committee of Çukurova University. ChemicalsIn this experimental study, three substances, including streptozotosin (STZ), furan, and lycopene, were administered; all chemicals used were obtained from Sigma. Furan and lycopene were dissolved in corn oil before being administered to the animals. Implementation plan for animalsChemicals were administered to the rats between 9:00 A.M. and 11:00 A.M. 55 mg/kg STZ was given to each rat by intraperitoneal (ip) injection as a single dose. Two days later, the blood glycose levels of the rats were measured. Rats with a glucose range of 300 mg/dL were accepted as diabetic. F...

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

Cited by 45 publications

References 16 publications

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

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

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

Furan toxicity on testes and protective role of lycopene in diabetic rats

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