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Plant-derived mycotoxin conjugates like deoxynivalenol-3-glucoside can be partly hydrolyzed to their aglycones in vivo, albeit to different extent depending on the mycotoxin conjugate and on the animal species. The aim of this work was to investigate the metabolization of the trichothecene mycotoxin nivalenol (NIV) and the fate of its modified form NIV-3-glucoside (NIV3G) in rats. To that end, 350 μg/kg body weight of NIV and the equimolar dose of NIV3G were administered to six rats by gavage in a 5 × 6 design and excreta were collected for 2 days after each treatment. For further analysis of NIV and NIV3G metabolites in rat urine and feces, seven novel NIV- and NIV3G metabolites including NIV sulfonates (NIVS) 1, 2 and 3, deepoxy-NIV (DNIV), DNIV sulfonate 2, NIV3G sulfonate (NIV3GS) 2 and NIV-3-glucuronide were produced, isolated and characterized. Subsequently, LC-MS/MS based methods for determination of NIV, NIV3G and their metabolites in excreta samples were developed, validated and applied. The biological recoveries of administered toxins in the form of their fecal and urinary metabolites were 57 ± 21% for NIV and 94 ± 36% for NIV3G. The majority of NIV and NIV3G metabolites was excreted into feces, with DNIV and NIVS 2 as major NIV metabolites and NIV3GS 2 and DNIV as major metabolites of NIV3G. Only 1.5% of the administered NIV3G was recovered in urine, with NIV3G itself as major urinary metabolite. The biological recovery of free NIV in urine was approximately 30 times lower after treatment with NIV3G than after administration of NIV, indicating that exposure of rats to NIV3G results in lower toxicity than exposure to NIV., (Copyright © 2019 The Author(s). Published by Elsevier B.V. All rights reserved.)

Anthocyanins are plant pigments occurring in flowers and berry fruits. Since a phenomenon of food-drug interactions is increasingly emerging, we examined the effects of 21 major anthocyanins and the extracts from 3 food supplements containing anthocyanins on the aryl hydrocarbon receptor (AhR)-cytochrome P450 CYP1A1 signaling pathway in human hepatocytes and human hepatic HepG2 and intestinal LS174T cancer cells. Pelargonidin-3-O-rutinoside (PEL-2) and cyanidin-3,5-O-diglucoside (CYA-3) dose-dependently activated AhR, as revealed by gene reporter assay. PEL-2 and CYA-3 induced CYP1A1 mRNA but not protein in HepG2 and LS174T cells. Neither compounds induced CYP1A1 mRNA and protein in four different primary human hepatocytes cultures. The effects of PEL-2 and CYA-3 on AhR occurred by ligand-dependent and ligand-independent mechanisms, respectively, as demonstrated by ligand binding assay. In a direct enzyme inhibition assay, none of the antocyanins tested inhibited the CYP1A1 marker activity to less than 50% even at 100 μM concentration. PEL-2 and CYA-3 at 100 μM inhibited CYP1A1 to 79% and 65%, respectively. In conclusion, with exception of PEL-2 and CYA-3, there were no effects of 19 major anthocyanins and 3 food supplements containing anthocyanins on AhR-CYP1A1 signaling, implying zero potential of these compounds for food-drug interactions with respect to AhR-CYP1A1 pathway., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Deoxynivalenol-3-β-D-glucoside (D3G), a plant metabolite of the Fusarium mycotoxin deoxynivalenol (DON), might be hydrolyzed in the digestive tract of mammals, thus contributing to the total dietary DON exposure of individuals. Yet, D3G has not been considered in regulatory limits set for DON for foodstuffs due to the lack of in vivo data. The aim of our study was to evaluate whether D3G is reactivated in vivo by investigation of its metabolism in rats. Six Sprague-Dawley rats received water, DON (2.0 mg/kg body weight (b.w.)) and the equimolar amount of D3G (3.1 mg/kg b.w.) by gavage on day 1, 8 and 15, respectively. Urine and feces were collected for 48 h and analyzed for D3G, DON, deoxynivalenol-glucuronide (DON-GlcA) and de-epoxy deoxynivalenol (DOM-1) by a validated LC-tandem mass spectrometry (MS/MS) based biomarker method. After administration of D3G, only 3.7±0.7% of the given dose were found in urine in the form of analyzed analytes, compared to 14.9±5.0% after administration of DON, and only 0.3±0.1% were detected in the form of urinary D3G. The majority of administered D3G was recovered as DON and DOM-1 in feces. These results suggest that D3G is little bioavailable, hydrolyzed to DON during digestion, and partially converted to DOM-1 and DON-GlcA prior to excretion. Our data indicate that D3G is of considerably lower toxicological relevance than DON, at least in rats., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Verminoside and verbascoside are natural compounds present in plants used in traditional medicine. They exhibit several biological activities including anti-inflammatory, anti-bacterial and anti-tumor properties. The potential applications of these compounds as ingredients in pharmaceutical formulations and cosmetics prompted us to investigate on cytotoxic and genotoxic activity of verminoside and verbascoside on human lymphocytes using genetic toxicity assays recommended in preclinical studies by the US Food and Drug Administration (FDA). We analyzed chromosome aberrations (CAs) and sister chromatid exchanges (SCEs) as well as the mitotic index (MI) and cell viability after the treatments with verminoside and verbascoside. This report is the first to clearly demonstrate a significant increase of structural CAs and SCEs on normal human lymphocytes associated with a reduction of the MI in both verminoside- and verbascoside-treated cells. Moreover, we observed enhanced protein expression levels of PARP-1 and p53 that are key regulatory proteins involved in cell proliferation and DNA repair. Interestingly, mass spectrometric analysis of the compounds in the culture supernatants also showed that verminoside remained unchanged during the culture period while verbascoside was hydrolyzed to its derivative, caffeic acid and the last one seems to be responsible for the observed biological activity.

The effects of stevioside and steviol (a product of enzymatic hydrolysis of stevioside) on intestinal glucose absorption were examined in hamster jejunum. By using the everted sac technique, we found that stevioside (1 and 5 mM) had no inhibitory effect on glucose absorption. In contrast, glucose absorption was inhibited 29% by 1 mM steviol. The inhibition of glucose absorption by steviol was related to steviol concentration and incubation time. The possible mechanism of steviol inhibitory action of glucose absorption was also investigated. Reductions in the intestinal mucosal ATP content and absorptive surface area were responsible for the inhibition of glucose absorption by steviol. The decrease in the intestinal mucosal ATP content was accompanied by a decrease in the activities of mitochondrial NADH cytochrome c reductase and cytochrome oxidase. Moreover, no inhibitory effects of steviol on the activity of intestinal Na+,K(+)-ATPase and glucose uptake in the intestinal brush-border membrane vesicles were seen. These results suggest that inhibition of intestinal glucose absorption by steviol in hamsters is due to the reduction in mucosal ATP content and an alteration of the morphology of the intestinal absorptive cells.

The toxicity of miserotoxin (3-nitro-1-propyl-beta-D-glucoside) and its aglycone, NPOH, were compared in rats. Miserotoxin, a component of certain legumes, was relatively innocuous given orally (LD50 greater than 2.5 g/kg) but NPOH (LD50 = 77 mg/kg) was at least 10 times more toxic. Miserotoxin was readily absorbed from the upper regions of the digestive tract but the degree of gastrointestinal hydrolysis was small. The low toxicity of miserotoxin was attributed to a low level of microbial hydrolysis. NPA was not detected in the gastrointestinal tract during miserotoxin digestion. A simple method for isolating miserotoxin by column chromatography is described.