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

Hamberger, Carolin; Kellert, Marco; Schauer, Ute M.D.; Dekant, W.; Mally, Angela

doi:10.1124/dmd.109.031781

Cited by 40 publications

(46 citation statements)

References 24 publications

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“…NAC-BDA-NAL is a significant metabolite detected in the urine of furan-treated rats (Kellert et al, 2008b;Lu et al, 2009). Data support the hypothesis that this compound is a downstream metabolite of degraded furan-derived protein adducts (Lu et al, 2009;Hamberger et al, 2010). Therefore, this metabolite can serve as a biomarker for furan exposure, metabolism, and bioactivation.…”

Section: Gates Et Alsupporting

confidence: 56%

“…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%

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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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Section: Gates Et Alsupporting

confidence: 56%

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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“…11 Thirteen percent of an 8 mg/kg dose of furan becomes bound to proteins 46 , therefore the degradation products of these adducts are expected to dominate in the urine and feces of furan-treated rodents. 10,11,47 Future studies will focus on the development of analytical methods to quantify each of the metabolites detected in the urine of furan-treated rats to get a better sense of the overall mass balance of the various pathways.…”

Section: Discussionmentioning

confidence: 99%

Polyamines Are Traps for Reactive Intermediates in Furan Metabolism

Peterson

Phillips

Ding

et al. 2011

Chem. Res. Toxicol.

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Furan is toxic and carcinogenic in rodents. Because of the large potential for human exposure, furan is classified as a possible human carcinogen. The detailed mechanism by which furan causes toxicity and cancer is not yet known. Since furan toxicity requires cytochrome P450-catalyzed oxidation of furan, we have characterized the urinary and hepatocyte metabolites of furan to gain insight into the chemical nature of the reactive intermediate. Previous studies in hepatocytes indicated that furan is oxidized to the reactive α,β-unsaturated dialdehyde, cis-2-butene-1,4-dial (BDA), which reacts with glutathione (GSH) to form 2-(S-glutathionyl)-succinaldehyde (GSH-BDA). This intermediate forms pyrrole cross-links with cellular amines such as lysine and glutamine. In this report, we demonstrate that GSH-BDA also forms cross-links with ornithine, putrescine and spermidine when furan is incubated with rat hepatocytes. The relative levels of these metabolites are not completely explained by hepatocellular levels of the amines or by their reactivity with GSH-BDA. Mercapturic acid derivatives of the spermidine cross-links were detected in the urine of furan-treated rats, which indicates that this metabolic pathway occurs in vivo. Their detection in furan-treated hepatocytes and in urine from furan-treated rats indicates that polyamines may play an important role in the toxicity of furan

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“…This vulnerability is attributed to its high capacity to bioactivate furan to the reactive intermediate, BDA, by cytP2E1. Furan’s hepatotoxicity effect might be attributed to its hepatocellular alterations and damages to the bile duct epithelium resulting in cholangiofibrosis and subsequent development of cholangiocarcinoma (Hamberger et al, ). Bialiary excretion is the major route for elimination of furan (Burka et al, ).…”

Section: Review Of Furan Toxicitymentioning

confidence: 99%

“…There are significant levels of CYP2E1 in lysosomes, plasma membrane, Golgi apparatus, peroxisome, and mitochondria. Moreover, the large amount of CYP2E1 is located in the endoplasmic reticulum (Hamberger, Kellert, Schauer, Dekant, & Mally, ). During this process, furan ring is opened; Z‐2‐butene‐1,4dialdehyde (BDA), an α,ß‐unsaturated di‐aldehyde (Kulkarni, Moir, & Zhu, ) and CO 2 are formed.…”

Section: Introductionmentioning

confidence: 99%

Industrial furan and its biological effects on the body systems

et al. 2018

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Furan as a product of thermal processing is found in many foods and beverages. In vitro and in vivo genotoxicity was positive for furan, also when metabolic preconditions for the formation of Z‐2‐butene‐1,4dialdehyde (BDA), the reactive compound, was met. However, in major studies, high doses represented the genotoxic effect. Moreover, data on toxicity in different cells and organs are inconsistent. For preparing remarkable risk assessments in human, providing bioassay data is necessary. We aimed to review available evidences about furan and BDA. A vast number of studies have been published on toxicity of furan in vitro and in vivo. Thus, we present a comprehensive review on the current status of furan in inducing toxic effects in different body systems, and possible mechanisms involved in the negative effects of this compound. In this article, furan mitigation procedures in foods have been taken into account. Practical applications From industrial point, furan is repeatedly used as an intermediate chemical in the process of producing some compounds such as resins, lacquers, pesticides and drugs. Furthermore, it is common as a side‐product of high‐energy radiation and thermal processes in food production. The current study focused on the effects of furan on the body organs. Furthermore, furan mitigation procedures in foods have been addressed in the current study. Nearly all previous studies on the industrial furan demonstrated that it has adverse health effects on the organs of the body. In order to prove specific results, further studies regarding furan risk assessment is of great importance.

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

Cited by 40 publications

References 24 publications

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

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

Polyamines Are Traps for Reactive Intermediates in Furan Metabolism

Industrial furan and its biological effects on the body systems

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