Elevation of Kynurenine Metabolites in Rat Liver and Serum: A Potential Additional Mechanism of the Alcohol Aversive and Anti-cancer Effects of Disulfiram?

Badawy, Abdulla A.-B.; Bano, Samina

doi:10.1093/alcalc/agv085

Cited by 10 publications

(4 citation statements)

References 33 publications

(46 reference statements)

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“…Adapted from Ref. 1. Badawy AA-B, Bano S. Elevation of kynurenine metabolites in rat liver and serum: a potential additional mechanism of the alcohol aversive and anti-cancer effects of disulfiram?…”

Section: Introductionmentioning

confidence: 99%

Tryptophan Metabolism in Rat Liver after Administration of Tryptophan, Kynurenine Metabolites, and Kynureninase Inhibitors

Badawy

Bano

2016

Int J�Tryptophan�Res

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Rat liver tryptophan (Trp), kynurenine pathway metabolites, and enzymes deduced from product/substrate ratios were assessed following acute and/or chronic administration of kynurenic acid (KA), 3-hydroxykynurenine (3-HK), 3-hydroxyanthranilic acid (3-HAA), Trp, and the kynureni-nase inhibitors benserazide (BSZ) and carbidopa (CBD). KA activated Trp 2,3-dioxygenase (TDO), possibly by increasing liver 3-HAA, but inhibited kynurenine aminotransferase (KAT) and kynureninase activities with 3-HK as substrate. 3-HK inhibited kynureninase activity from 3-HK. 3-HAA stimulated TDO, but inhibited kynureninase activity from K and 3-HK. Trp (50 mg/kg) increased kynurenine metabolite concentrations and KAT from K, and exerted a temporary stimulation of TDO. The kynureninase inhibitors BSZ and CBD also inhibited KAT, but stimulated TDO. BSZ abolished or strongly inhibited the Trp-induced increases in liver Trp and kynurenine metabolites. The potential effects of these changes in conditions of immune activation, schizophrenia, and other disease states are discussed.

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Section: Introductionmentioning

confidence: 99%

Tryptophan Metabolism in Rat Liver after Administration of Tryptophan, Kynurenine Metabolites, and Kynureninase Inhibitors

Badawy

Bano

2016

Int J�Tryptophan�Res

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“…The ability of DSF to influence the hepatic tryptophan/kynurenine pathway may represent an alternative mechanism to combat diet-induced insulin resistance 35 . Data from an earlier work showed that DSF administration in rats allows for the accumulation of serum 3-HAA 36 . Here we observed a significant reduction in tryptophan metabolites, anthranilic acid, and 3-HAA, in serum of DSF-treated rats together with altered expression of two key enzymes implicated in hepatic tryptophan catabolism, IDO2 and KYNU, with the latter being involved in the kynurenine pathway for NAD biosynthesis and redox reactions 37 .…”

Section: Resultsmentioning

confidence: 97%

Elucidating the mechanisms by which disulfiram protects against obesity and metabolic syndrome

et al. 2020

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There is an unmet need and urgency to find safe and effective anti-obesity interventions. Our recent study in mice fed on obesogenic diet found that treatment with the alcohol aversive drug disulfiram reduced feeding efficiency and led to a decrease in body weight and an increase in energy expenditure. The intervention with disulfiram improved glucose tolerance and insulin sensitivity, and mitigated metabolic dysfunctions in various organs through poorly defined mechanisms. Here, integrated analysis of transcriptomic and proteomic data from mouse and rat livers unveiled comparable signatures in response to disulfiram, revealing pathways associated with lipid and energy metabolism, redox, and detoxification. In cell culture, disulfiram was found to be a potent activator of autophagy, the malfunctioning of which has negative consequences on metabolic regulation. Thus, repurposing disulfiram may represent a potent strategy to combat obesity.

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“…to male Wistar rats, since Cd delivery into the blood stream is almost equal to inhalation route26 , 27. The applied dose of 1 mg CdCl 2 /kg/day was chosen according to the literature24 , 25, while per os dose of 178.5 mg DSF/kg BW/day corresponds to the lowest maintaining dose of 125 mg per tablet given in therapy of recovering alcoholics28 , 29.…”

Section: Discussionmentioning

confidence: 99%

Disulfiram moderately restores impaired hepatic redox status of rats subchronically exposed to cadmium

Begić

Djurić

Ninković

et al. 2017

Journal of Enzyme Inhibition and Medicinal Chemistry

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Examination of cadmium (Cd) toxicity and disulfiram (DSF) effect on liver was focused on oxidative stress (OS), bioelements status, morphological and functional changes. Male Wistar rats were intraperitoneally treated with 1 mg CdCl2/kg BW/day; orally with 178.5 mg DSF/kg BW/day for 1, 3, 10 and 21 days; and co-exposed from 22nd to 42nd day. The co-exposure nearly restored previously suppressed total superoxide dismutase (SOD), catalase (CAT) and increased glutathione peroxidase (GPx) activities; increased previously reduced glutathione reductase (GR) and total glutathione-S-transferase (GST) activities; reduced previously increased superoxide anion radical (O2 ·−) and malondialdehyde (MDA) levels; increased zinc (Zn) and iron (Fe), and decreased copper (Cu) (yet above control value), while magnesium (Mg) was not affected; and decreased serum alanine aminotransferases (ALT) levels. Histopathological examination showed signs of inflammation process as previously demonstrated by exposure to Cd. Overall, we ascertained partial liver redox status improvement, compared with the formerly Cd-induced impact.

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Elevation of Kynurenine Metabolites in Rat Liver and Serum: A Potential Additional Mechanism of the Alcohol Aversive and Anti-cancer Effects of Disulfiram?

Cited by 10 publications

References 33 publications

Tryptophan Metabolism in Rat Liver after Administration of Tryptophan, Kynurenine Metabolites, and Kynureninase Inhibitors

Tryptophan Metabolism in Rat Liver after Administration of Tryptophan, Kynurenine Metabolites, and Kynureninase Inhibitors

Elucidating the mechanisms by which disulfiram protects against obesity and metabolic syndrome

Disulfiram moderately restores impaired hepatic redox status of rats subchronically exposed to cadmium

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