Kinetic Analysis of Furan Biotransformation by F-344 Rats in Vivo and in Vitro

Kedderis, Gregory L.; Carfagna, Mark A.; Held, S D; Batra, Renu; Murphy, J E; Gargas, Michael L.

doi:10.1006/taap.1993.1246

Cited by 126 publications

(74 citation statements)

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“…Furan is oxidized by cytochrome P450 (P450) enzymes to the reactive metabolite cis-2-butene-1,4-dial [(BDA) Scheme 1] (Chen et al, 1995;Peterson et al, 2005). 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.…”

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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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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“…Both in vitro and in vivo studies show that metabolic activation by cytochrome P450 (CYP) enzymes is involved in furan-induced toxicity. Inhibition and induction experiments revealed that CYP2E1 is the major enzyme involved in furan biotransformation indicating that furan metabolism can be enhanced by pre-treatment of rats with acetone (induction of CYP2E1) but not with phenobarbital (induction of CYP2B2 isozymes) (Kedderis et al 1993). However, Kedderis and Held (1996) concluded that even the induction of hepatic CYP2E1 would not affect the rate of hepatic metabolism because the metabolic capacity of CYP2E1 for furan is so high that hepatic blood flow is the rate-limiting step in the elimination of the parent compound.…”

Section: Metabolism and Toxicology Of Furanmentioning

confidence: 99%

Furan in food - a review

Vránová¹,

Ciesarová²

2009

Czech J. Food Sci.

108

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Furan and its derivatives were identified in a small number of heat-treated foods back in the 60's and 70's. In May 2004, US Food and Drug Administration published a report on the occurrence of parent furan in a number of thermally treated foods. Since furan has been classified as "possibly carcinogenic to human" by IARC, a great concern has been addressed to the analysis of this substance naturally-occurring in food. This paper gives a short overview on the mechanistic pathways of the parent furan formation in food by degradation of amino acids and/or reducing sugars, and oxidation of ascorbic acid and poly-unsaturated acids which can be induced by thermal or irradiation treatments; further, it deals with the metabolism and toxicology of furan as well as with the comparison of the methods of furan determination.

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“…Precision-cut liver slices retain the architecture of the liver and the interactions between different cell types, but problems with diffusion of substrates and nutrients into the slices make in vivo extrapolation of the in vitro data problematic (Ekins et al, 1995;Worboys et al, 1996). Isolated hepatocytes have been shown to be the system of choice for in vitro prediction of pharmacokinetics (Kedderis et al, 1993;Houston, 1994) since the cells maintain a biochemical homeostasis of cofactors and enzymes similar to the intact liver. While freshly isolated hepatocytes suspended in a nutritive medium catalyze xenobiotic biotransformation reactio ns similarly to the liver in vivo (Billings et al, 1977), hepatocytes in monolayer culture rapidly differentiate and decrease xenobiotic metabolism capabilities (Sirica & Pitot, 1980).…”

Section: In Vitro Biotransformation Systemsmentioning

confidence: 99%

“…In vitro kinetic data from hepatocytes were used to develop PBPK models for furan in rats (Kedderis et al, 1993), mice, and humans (Kedderis and Held, 1996). Simulation of inhalation exposure to 10 ppm furan for 4 h indicated that the absorbed dose of furan (mg/kg; inhaled minus exhaled divided by body weight) and the integrated exposure of the liver to the toxic metabolite were approximately 3.5-fold and 10-fold greater in rats and mice, respectively, than in humans.…”

Section: Examples Of In Vitro To In Vivo Extrapolationmentioning

confidence: 99%

Incorporation of Pharmacokinetic and Pharmacodynamic Data into Risk Assessments

Lipscomb

Meek

Krishnan³

et al. 2004

Toxicology Mechanisms and Methods

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Risk assessment methodologies are being updated to allow the inclusion of numerical values for variance in pharmacokinetic (PK) measures and pharmacodynamic (PD) processes related to toxicity. The key PK measures and PD processes are identified from the results of carefully conducted and adequately reported studies. In some instances, studies with humans are not possible, and so the development of data useful for human PK evaluations and on PD processes in vitro or in silico represent an alternative. These results can be integrated under physiologic, anatomic and biochemical constraints of the intact body through physiologically based pharmacokinetic (PBPK) modeling. This manuscript presents the rational for and key considerations related to the inclusion of quantitative PK and PD data in assessing chemical risks.2

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Kinetic Analysis of Furan Biotransformation by F-344 Rats in Vivo and in Vitro

Cited by 126 publications

References 0 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

Furan in food - a review

Incorporation of Pharmacokinetic and Pharmacodynamic Data into Risk Assessments

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