Oxidative Metabolites of 5-Nitrofurans

Streeter, Anthony J.; Krueger, Terry R.; Hoener, Betty‐Ann

doi:10.1159/000138396

Cited by 7 publications

(5 citation statements)

References 6 publications

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“…These results suggest that the increase in the metabolic rate of FZ may be associated with CPR activity in chicken liver microsomes. However, previous reports suggested that the increase in the metabolic rate of FZ was attributable to CYPs [34,51]. Actually, we observed two-fold elevation of CYP2C subfamily protein expression in liver of FZ treated chickens (data not shown).…”

Section: Discussioncontrasting

confidence: 47%

Furazolidone induces the activity of microsomal enzymes that metabolize furazolidone in chickens

Sasaki

Matsumoto

Ikenaka

et al. 2011

Pesticide Biochemistry and Physiology

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The nitrofuran antibacterial agent furazolidone (FZ) is still used in veterinary medicine in some countries in the Middle and Far East. The present study aimed to show the effect of FZ on the activity of microsomal enzymes that metabolize FZ, and to identify the enzyme that contributes to FZ metabolism in chickens. Wistar rats and White Leghorn chickens were administered FZ once a day for 4 consecutive days. FZ metabolism was accelerated by FZ administration in chickens, but not in rats. The elevation of FZ metabolism coincided with the induction of NADPH cytochrome P450 reductase (CPR) activity in chickens, but such induction was not observed in rats. FZ metabolizing activities were inhibited in the presence of a CPR inhibitor (diphenylene iodonium chloride) but not by the addition of archetypal cytochrome P450 inhibitors (CO or n-octylamine). The preset study concluded that FZ accelerated its own metabolism in the chicken by induction of the activity of CPR.

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Section: Discussioncontrasting

confidence: 47%

Furazolidone induces the activity of microsomal enzymes that metabolize furazolidone in chickens

Sasaki

Matsumoto

Ikenaka

et al. 2011

Pesticide Biochemistry and Physiology

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“…Whether the active form of furazolidone against P. carinii is the parent compound or some metabolite is unknown. Furazolidone is actively metabolized probably both in the intestine and in the liver; nitro reduction to the aminofuran is the major route, but other pathways may also exist (30,32,39).…”

Section: Discussionmentioning

confidence: 99%

Furazolidone and nitrofurantoin in the treatment of experimental Pneumocystis carinii pneumonia

Walzer

Kim

Foy

et al. 1991

Antimicrob Agents Chemother

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Furazolidone and nitrofurantoin, oral nitrofuran derivatives with broad-spectrum antimicrobial properties already in clinical use, were compared for activity against Pneumocystis carinii in an immunosuppressed rat model of P. carinii pneumonia. Furazolidone exhibited only slight activity as a prophylactic agent but was moderately effective in the therapy of pneumocystosis. The median histologic score and organism count fell from 4+ and and their toxic effects on the rats will probably discourage investigation of this drug in the treatment of pneumocystosis in humans. Nevertheless, since many nitrofurans have been synthesized, further exploration of this class of compounds might be helpful in developing new anti-P. carinii agents or in studying structureactivity relationships.Pneumocystis carinii is a leading cause of pneumonia in immunosuppressed patients. The incidence of pneumocystosis has increased markedly over the past decade in association with the emergence of AIDS (34). Treatment of P. carinii pneumonia in AIDS patients has been hindered by a high frequency of recurrence and of toxic reactions to antimicrobial drugs. Anti-P. carinii compounds currently in clinical use include inhibitors of dihydrofolate reductase (e.g., trimethoprim [TMP], trimetrexate), sulfonamides (sulfamethoxazole [SMX]), and sulfones (dapsone); diamidines (pentamidine isethionate); polyamine inhibitors (adifluromethylornithine); and the combination of clindamycin and primaquine (2,11,13,21,27).Our laboratory has been engaged in developing new forms of P. carinii therapy for the past several years (8,15,35,36). Drug selection has been hampered by the lack of knowledge about the metabolic pathways of the organism. Studies are conducted in an animal model in which rats given corticosteroids spontaneously develop pneumocystosis by a process of reactivation of latent infection. Although this system permits evaluation of relatively few compounds, it has been a reliable predictor of drug activity in humans (10, 12).Here we report our experience with two nitrofuran derivatives, furazolidone and nitrofurantoin. Nitrofurans possess broad antimicrobial properties, including activity against trypanosomes (4,20,25,26,29,31). Our rationale for testing them against P. carinii was based on the following considerations. First, several classes of drugs (e.g., diamidines, polyamine inhibitors, purine nucleosides) with antitrypanosomal properties have been shown to be effective against P. carinii, although the specific mechanisms of action are unknown (8,21,28,36). Second, since furazolidone and nitrofurantoin are oral preparations and are already in clinical use, they would be much easier to develop as anti-P. carinii drugs than would unlicensed compounds with poorly * Corresponding author. understood pharmacokinetic properties or toxicological profiles. MATERIALS AND METHODSExperimental design. (i) Treatment. The animal protocol that we used has been described in detail previously (15,(35)(36)(37). In brief, adult male Sprague-Dawley rats (Harlan I...

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“…In experiments carried out with the isolated perfused rat liver (Hoener, 1988), the nitrofurazonemediated oxidative stress induced by both the nitroanion redox cycling and the generation of further reactive unstable reduced metabolites (see Section 8.1.1) could be inferred by the marked increase in biliary glutathione-disulphide (GSSG) along with a marked decline of tissue GSH levels. Using 35 S-methionine, a GSH adduct with nitrofurazone (or its metabolites) could be identified by means of HPLC.…”

Section: Laboratory Animalsmentioning

confidence: 99%

“…Furaltadone is reported to undergo N-oxidation of the tertiary nitrogen of the morpholino ring in pig hepatocytes; interestingly, the resulting N-oxide derivative is not subjected to further metabolism to an open-chain nitrile derivative, which is instead produced upon the incubation of furaltadone with S. Typhimurium bacteria (Hoogenboom et al, 1994). Finally, the isolation of urinary 4-hydroxylated derivatives of a number of nitrofurans has also been reported in rats, rabbits, swine and chickens (Swaminathan and Lower, 1978;Streeter et al, 1988). There is a general consensus that the nitroreductive pathway is clearly linked to the bioactivation of nitrofurans.…”

Section: Non-dietary Exposurementioning

confidence: 99%

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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Oxidative Metabolites of 5-Nitrofurans

Cited by 7 publications

References 6 publications

Furazolidone induces the activity of microsomal enzymes that metabolize furazolidone in chickens

Furazolidone induces the activity of microsomal enzymes that metabolize furazolidone in chickens

Furazolidone and nitrofurantoin in the treatment of experimental Pneumocystis carinii pneumonia

Scientific Opinion on nitrofurans and their metabolites in food

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