Study on the role of glutathione in the biotransformation and toxicity of furazolidone using pig hepatocytes

Hoogenboom, L.A.P.; Kammen, M. van; Huveneers-Oorsprong, M.B.M.; Kuiper, H.A.

doi:10.1016/0887-2333(92)90036-q

Cited by 12 publications

(5 citation statements)

References 30 publications

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“…The FDA has expressed concern for this possibility and now requires that an assessment of the gastro intestinal binding potential of released bound residues be part of an overall residue assessment (SOM Final Rule, 1987; FDA Guidelines, 1990). The generation of reactive conjugates of furazolidone metabolites has been reported in microsomal incubations (Vroomen et al, 1988b); however, this could not be confirmed using hepatocytes (Hoogenboom et al, 1992a), possibly due to their instability. The glutathione and mercaptoethanol adducts of furazolidone, isolated from microsomal incubations, were also tested and shown to be negative in the Salmonella mutagenicity (Ames) test.…”

Section: Resultsmentioning

confidence: 95%

Depletion and Bioavailability of [14C]Furazolidone Residues in Swine Tissues

Gottschall¹,

Wang²

1995

J. Agric. Food Chem.

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Six swine (three male, three female) were dosed orally with [14Clfurazolidone for 14 days a t a dose level of 16.5 mg kg-l day-l. At 0-day (10-h) withdrawal, liver contained the highest residues (41.1 ppm) followed by kidney (34.4), muscle (13.21, and fat (6.2). M e r a 45-day withdrawal, all tissues had total residues of approximately 2.0 ppm. The amount of aminooxazolidinone (AOZ) released from the bound tissue residues, on average, represented 7.5% of the total residues. Additional tissue samples were lyophilized, pelleted, and fed to rats for determination of bound residue bioavailability using the Gallo-Torres model. Bioavailability of liver residues decreased from 40% at 0-day withdrawal to 19% after 45 days, while muscle residues showed no change in relative bioavailability with corresponding values of 37% and 41%. Pretreatment of tissue samples with organic solvents to generate a nonextractable pellet removed 10-20% of the initial radioactivity but had no effect on the overall bioavailability of the remaining residues.

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Section: Resultsmentioning

confidence: 95%

Depletion and Bioavailability of [14C]Furazolidone Residues in Swine Tissues

Gottschall¹,

Wang²

1995

J. Agric. Food Chem.

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“…While the redox cycling of the nitroanion and/or the nitroso intermediates are mainly involved in the generation of oxidant species, other pathways such as the related alteration of the NADP+ to NADPH ratio and the depletion of glutathione (GSH) and of other critical thiol groups may participate in the enhancement of the nitrofuran-mediated oxidative stress (Boelsterli et al, 2006). GSH and other thiols may prevent the formation of certain reactive nitrofuran derivatives (Lax and Kukolich, 1992) and, under certain conditions, may also be depleted upon in vitro exposure to certain nitrofurans (Hoogenboom et al, 1992b;De Angelis et al, 1999). However, it should be noted that the nature of the reactive chemical species which bind to thiol groups has yet to be fully elucidated (and may vary with the different compounds).…”

Section: Non-dietary Exposurementioning

confidence: 99%

“…While the formation of GSH conjugates with nitroso-or hydroxylamino-derivatives cannot be excluded, in vitro studies with swine liver microsomes or hepatocytes suggest that, in the case of furazolidone, an open-chain acrylonitrile derivative identified as N-(4-cyano-2-oxo-3-butenylidene)-3amino-2-oxazolidinone may be trapped by thiol-containing compounds such as GSH or mercaptoethanol (Vroomen et al, 1987b;Hoogenboom et al, 1992b) leading to the formation of unstable reversible conjugates. In fact, at physiological pH, the acrylonitrile derivative may be released and become covalently bound to cellular proteins forming protein adducts (Hoogenboom et al, 1992b). When incubated with thiols, the acrylonitrile derivative can be released from the protein again.…”

Section: Non-dietary Exposurementioning

confidence: 99%

“…Furazolidone (Jin et al, 2011), but also AOZ and AMOZ (Zolla et al, 2005) and SEM (Hirakawa et al, 2003) caused DNA damage and DNA fragmentation in in vitro systems by the production of ROS, which could be ameliorated by addition of catalase or superoxide dismutase. These oxygen radicals can be detoxified by GSH resulting in the formation of the oxidised form, GSSG, and potentially increased synthesis and even depletion of GSH levels in the cell (Hoogenboom et al, 1992b). Antioxidants such as vitamin E and selenium may also protect against damage (Boyd et al, 1979;Peterson et al, 1982), whereas polyunsaturated fatty acids, for example, may exaggerate the effects (Boyd et al, 1979).…”

Section: Modes Of Actionmentioning

confidence: 99%

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Scientific Opinion on nitrofurans and their metabolites in food

Panel¹

2015

EFS2

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Nitrofurans are antimicrobial agents not authorised for use in food-producing animals in the European Union. Nitrofurans are rapidly metabolised, occurring in animal tissues as protein-bound metabolites. The European Commission requested EFSA to provide a scientific opinion on the risks to human health related to the presence of nitrofurans in food and whether a reference point for action (RPA) of 1.0 µg/kg for the marker metabolites is adequate to protect public health. Data on occurrence of nitrofuran marker metabolites in food were extracted from the national residue monitoring plan results and from the Rapid Alert System for Food and Feed (RASFF). The CONTAM Panel concluded that these data were too limited to carry out a reliable human dietary exposure assessment. Instead, human dietary exposure was calculated for a scenario in which a single nitrofuran marker metabolite is present at 1.0 µg/kg in foods of animal origin, excluding milk and dairy products. The mean chronic dietary exposure for this worst-case scenario would range from 3.3 to 8.0 and 1.9 to 4.3 ng/kg b.w. per day for toddlers and adults, respectively. Nitrofurans and their marker metabolites, generally, are genotoxic and carcinogenic and, also, have non-neoplastic effects in animals. Margins of exposure (MOEs) were calculated at 2.0 × 10 5 or greater for carcinogenicity and at 2.5 × 10 3 or greater for non-neoplastic effects. The CONTAM Panel concluded that it is unlikely that exposure to food contaminated with nitrofuran marker metabolites at or below 1.0 µg/kg is a health concern. A scenario in which foods are considered to be contaminated with semicarbazide, from use of carrageenan as a food additive, at 1 µg/kg was used to assess whether it is appropriate to apply the RPA to foods of non-animal origin; MOEs of greater than 10 4 calculated for nonneoplastic effects do not indicate a health concern.© European Food Safety Authority, 2015 However, the opinion also identified certain categories of non-allowed pharmacologically active substances that are considered to be outside the scope of the procedure, including substances that are high potency carcinogens, such as nitrofurans. As nitrofurans are excluded from that opinion, and taking into account that the presence of SEM in food may be from sources other than use of nitrofurazone, the European Commission (EC) requested the European Food Safety Authority (EFSA) for a scientific opinion on the risks to human health related to the presence of nitrofurans and their metabolites in food. The opinion should include (a) an evaluation of the toxicity of nitrofurans and their metabolites for humans, considering all relevant toxicological endpoints and identification of the toxicological relevance of nitrofurans and their metabolites present in food, and (b) an exposure assessment of the EU population to nitrofurans and their metabolites from food, including the consumption patterns of specific (vulnerable) groups of the population. In addition, the opinion should assess the appropriateness of...

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“…Regarding the fact that, 48 h after the last treatment, the parent compound and the two metabolites mentioned above could no longer be detected in plasma and tissues, such bound metabolites may eventually become the most important residues. Previously, we described the isolation of pig hepatocytes from a sample of pig liver and their successful use for studying the biotransformation of the veterinary drugs furazolidone, furaltadone, and sulfadimidine (Hoogenboom et al, 1989(Hoogenboom et al, , 1991(Hoogenboom et al, , 1992(Hoogenboom et al, , 1994. The aim of the present study was to further evaluate the possibilities of this model for predicting the in vivo metabolism of drugs by investigating the biotransformation of DMZ, including the formation of protein-bound metabolites.…”

Section: Introductionmentioning

confidence: 99%

Biotransformation of Dimetridazole by Primary Cultures of Pig Hepatocytes

Hoogenboom¹,

Polman²,

Rhijn³

et al. 1997

J. Agric. Food Chem.

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Monolayer cultures of pig hepatocytes were used to investigate the role of the liver in the biotransformation of the veterinary drug dimetridazole (1,2-dimethyl-5-nitroimidazole). 14C-Labeled dimetridazole (DMZ) was primarily hydroxylated to 1-methyl-2-hydroxymethyl-5-nitroimidazole (up to 90%) and to a minor extent N-demethylated to 2-methyl-(4,5)-nitroimidazole (6−10%). Prolonged incubation with the parent drug but also the 2-hydroxymethyl metabolite resulted in the formation of two other minor metabolites. The major one of these was identified as the glucuronide of the 2-hydroxymethyl metabolite, based on its molecular mass and the succesful hydrolysis with β-glucuronidase. The second showed a molecular mass of 144 and is hypothesized to be 2-hydroxymethyl-5-nitroimidazole. No evidence was obtained for the formation of a cysteine or glutathione conjugate involved in the detoxification of reactive intermediates. In addition to free metabolites, there was a time-related formation of protein-bound metabolites up to a maximum of 30 pmol/mg of protein after exposure to 50 μM DMZ for 48 h. In general, these metabolites accounted for 0.06−0.15% of the metabolized DMZ. Unextractable metabolites were also observed after incubation of cells with the 2-hydroxymethyl and 1-desmethyl metabolites. It is concluded that the 1-desmethyl and, in particular, the 2-hydroxymethyl metabolite are the major metabolites formed by pig hepatocytes. These compounds are thus far the only metabolites identified in vivo, but together with the parent compound, they accounted for only a small part (<5%) of the excreted drug. Therefore, the site of formation of the majority of the unknown in vivo metabolites may be extrahepatic, and complimentary models are needed to investigate this hypothesis. Keywords: Pig hepatocytes; dimetridazole; nitroimidazoles; bound residues

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Study on the role of glutathione in the biotransformation and toxicity of furazolidone using pig hepatocytes

Cited by 12 publications

References 30 publications

Depletion and Bioavailability of [14C]Furazolidone Residues in Swine Tissues

Depletion and Bioavailability of [14C]Furazolidone Residues in Swine Tissues

Scientific Opinion on nitrofurans and their metabolites in food

Biotransformation of Dimetridazole by Primary Cultures of Pig Hepatocytes

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