Absorption, Distribution and Excretion
Nivalenol is rapidly distributed to and eliminated from all examined tissues in mice with no apparent accumulation in any organ.
After long term oral administration of nivalenol to male rats, the dose was recovered as fecal nivalenol (7%), fecal de-epoxy nivalenol (80%), urinary nivalenol (1%) and urinary de-epoxy nivalenol (1%).
In order to investigate the comparative fates of nivalenol (NIV) and 4-acetyl derivative of NIV (fusarenon-X, FX) in mice, (3)H-FX or (3)H-NIV was given p.o. to mice. Radioactivity was excreted mainly via the urine in mice given (3)H-FX, but mainly via the feces in mice given (3)H-NIV. The plasma radioactivity reached a peak at 30 or 60 min after the administration of (3)H-FX or (3)H-NIV, respectively. The plasma peak level was 5 times higher, and the area under curve (AUC) was 10 times higher, in (3)H-FX-administered than (3)H-NIV-administered mice. These findings clearly demonstrate that FX is absorbed from the gastrointestinal tract more rapidly and efficiently than NIV. The HPLC profile of radioactivity of acetonitrile extracts of urine and feces indicated that FX is rapidly metabolized to NIV after being absorbed from the gastrointestinal tract. In vitro incubation of tissue homogenates with (3)H-FX demonstrated that the liver and kidney are the organs responsible for the FX-to-NIV conversion. Thus this study demonstrated that the higher oral toxicity of FX than NIV that has been observed in mice and rats is due to the efficient absorption of FX than NIV from the gastrointestinal tract, followed by its rapid conversion to NIV by the liver and kidney.

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Metabolism / Metabolites
There is evidence of major species-dependent differences in the extent of de-epoxidation of nivalenol in non-ruminants, which may occur in the lower parts of the gastrointestinal tract in some species. The de-epoxy metabolite has been detected in feces of rats, pigs and laying hens, but not in mice or broiler chickens and, based on in vitro studies, it is unlikely to be formed in humans.
In ruminants, it is likely that, as for other trichothecenes, extensive de-epoxidation of nivalenol may occur in the rumen prior to absorption.
Nivalenol is metabolized to de-epoxy nivalenol.
The cytotoxicity of the de-epoxy metabolites of trichothecenes nivalenol (NIV) and deoxynivalenol (DON) was determined and compared with the cytotoxicity of the respective toxin with an intact epoxy group and their acetylated derivatives. The cytotoxic effects was determined by using the 5-bromo-2'-deoxyuridine (BrdU) incorporation assay assessing DNA-synthesis. The toxicity of NIV and DON expressed as the concentration inhibiting 50% of the DNA synthesis (IC(50)), was occurring at similar micromolar concentrations (1.19+/-0.06 and 1.50+/-0.34 uM). The toxicity of fusarenon X (4-acetyl NIV) in the assay was similar to the toxicity of NIV, and the toxicity of 15-AcDON was equal to the toxicity of DON. 3-AcDON was less toxic than DON and 15-AcDON. The IC(50) value for de-epoxy DON was 54 times higher in the assay than the IC(50) for DON, while the IC(50) of de-epoxy NIV was 55 times higher than the IC(50) for NIV. The results verify previous findings that the de-epoxidation is a detoxification reaction.

Interactions
A feeding trial was conducted in order to determine the effects of a Fusarium poae extract on the health and performances of broiler chickens and the possible protective effect of a natural zeolite. The F. poae extract contained nivalenol, T-2 toxin and diacetoxyscirpenol and demonstrated high toxicity when administered i.p. to rats. One-day-old broiler chickens were fed ad libitum over a period of 28 days with the following diets: group I - control; group II - 0.5% zeolite; group III -F. poae extract; group IV-0.5% zeolite andF. poae extract. Broilers were sacrificed at 28 days for the measurement of relative organs weights, leukocyte counts and serum biochemical values. No mortality was recorded over the experiment. Body weight gains, feed intake, feed utilization and water consumption were depressed by the F. poae extract (p<0.05). A decrease of these parameters was also observed in group IV which received the diet with zeolite and the F. poae extract. No significant differences were seen in group II when compared to control. In groups III and IV the relative weights of liver, kidney, heart and gizzard were significantly increased (p<0.05), while in group II only the relative liver weight was increased. F. poae extract, administered singly or in combination with zeolite, significantly decreased leukocytes count, serum total protein and serum albumin. Zeolite and F. poae extract, singly or combined, increased serum creatinine and uric acid concentrations (p<0.05). These findings indicate that sublethal doses of F. poae extract can affect adversely the performances and the health in broiler chickens. By adding zeolite these impairments could not be diminished and for some parameters the zeolite additive increased the adverse effects of the F. poae extract.
Deoxynivalenol (DON) and nivalenol (NIV) are toxic Fusarium secondary trichothecene metabolites that often co-occur regularly in cereal grains. These compounds were compared for their toxicity towards C57BL/6 mice on several parameters including alteration in plasma biochemistry, immune system reactivity and hepatic drug metabolism capacity. Mice received individual or combined oral doses of each toxin: 0.071 or 0.355 mg/kg of body weight, administrated three days a week for 4 weeks. Food consumption was altered by the single administration of 0.355 mg/kg of NIV, although no noticeable change of body and organ weights or liver protein contents was detected. NIV administration did cause also significant changes in total CO2 and uric acid concentrations in plasma. Individual toxin exposures led to increases in plasma IgA without no detectable change in the ex vivo production of cytokine by splenocytes. The liver ethoxyresorufin O-deealkylase, pentoxyresorufin O-depenthylase and glutathione S-transferase activities were increased in concert with cytochrome P4501a and P4502b subfamily expression. Administration of combinations of DON and NIV resulted in responses similar to that observed using individual doses of each toxin. However, depending on the ratio of toxin doses and biochemical parameters, some responses could be also additive (plasma IgA and hepatic DCNB conjugation) or synergistic (plasma uric acid).
Deoxynivalenol (DON) is the most prevalent trichothecene mycotoxin in crops in Europe and North America. DON is often present with other type B trichothecenes such as 3-acetyldeoxynivalenol (3-ADON), 15-acetyldeoxynivalenol (15-ADON), nivalenol (NIV) and fusarenon-X (FX). Although the cytotoxicity of individual mycotoxins has been widely studied, data on the toxicity of mycotoxin mixtures are limited. The aim of this study was to assess interactions caused by co-exposure to Type B trichothecenes on intestinal epithelial cells. Proliferating Caco-2 cells were exposed to increasing doses of Type B trichothecenes, alone or in binary or ternary mixtures. The MTT test and neutral red uptake, respectively linked to mitochondrial and lysosomal functions, were used to measure intestinal epithelial cytotoxicity. The five tested mycotoxins had a dose-dependent effect on proliferating enterocytes and could be classified in increasing order of toxicity: 3-ADON<15-ADON =~ DONMolded and mycotoxin containing barley was incorporated into the diets for laying hens to study the effects on performance and health. Health indicators were different blood plasma parameters and liver vitamin A and E levels. A total of 30 hens were fed 3 diets, one supplemented with 30% of toxin-free and two with differently molded barley from 1997 and 1998 for 7 weeks. The molded diets contained low to moderate concentrations of ochratoxin A, zearalenone, deoxynivalenol and nivalenol. Inclusion of moldy barley in the diets had an adverse effect on feed intake, feed conversion, digestibility of nutrients, egg production and egg quality. Plasma alkaline phosphatase was increased and certain biochemical blood parameters (bilirubin, uric acid, chloride, protein, albumin, vitamin A) were also higher or changed compared to control. The ochratoxin A contamination although relatively low could have contributed to some of these effects as well as reduced intake of feed. The higher mold contamination and an unidentified cell-toxic constituent in the diet containing barley from 1998 can probably also explain the more marked effects from this diet.
/ALTERNATIVE and IN VITRO TESTS/ Nivalenol (NIV) and Deoxynivalenol (DON), mycotoxins of the trichothecene family are considered very common food contaminants. In this work, /the authors/ investigated whether the immunotoxic effects ascribed to these trichothecenes may be mediated by perturbations in the activity of dendritic cells (DCs). Murine bone marrow-derived DCs were used to evaluate the effects of NIV and DON on the LPS-induced maturation process. /The authors/ found that the expression of the class II MHC and of the accessory CD11c molecules, but not of the costimulatory CD86 marker, was down-regulated by NIV and DON exposure in LPS-treated DCs, as well as nitric oxide (NO) production. Interestingly, NIV, but not DON, induced DC necrosis. Moreover, the analysis of the cytokine pattern showed that IL-12 and IL-10 expressions induced by LPS exposure were suppressed by both trichothecenes in a dose-dependent fashion. On the other hand, the secretion of the proinflammatory cytokine TNF-alpha was increased as a direct consequence of DON and NIV exposure. Taken together, /this/ data indicated that the immunotoxicity of NIV and DON was related to the capacity of both trichothecenes to interfere with phenotypic and functional features of maturing DCs.

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Non-Human Toxicity Values
LD50 Mouse oral 38.9 mg/kg
LD50 Mouse ip 7.4 mg/kg
LD50 Mouse sc 7.2 mg/kg
LD50 Mouse iv 7.3 mg/kg
For more Non-Human Toxicity Values (Complete) data for NIVALENOL (6 total), please visit the HSDB record page.

[1]. Natural Occurrence of Nivalenol, Deoxynivalenol, and Deoxynivalenol-3-Glucoside in Polish Winter Wheat. Toxins (Basel). 2018 Feb 13;10(2).

[2]. Individual and combined mycotoxins deoxynivalenol, nivalenol, and fusarenon-X induced apoptosis in lymphoid tissues of mice after oral exposure. Toxicon. 2019 Jul;165:83-94.

12,13-Epoxy-3,4,7,15-tetrahydroxytrichothec-9-en-8-one has been reported in Fusarium graminearum, Fusarium culmorum, and Fusarium tricinctum with data available.

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Mechanism of Action
Trichothecenes, such as nivalenol, inhibit peptidyl transferase with subsequent inhibition of peptide bond formation. The target organelle of trichothecene action is the 60S subunit of eukaryotic ribosomes, the protein inhibition activity correlating well with ribosome affinity. The mechanism of protein inhibition can be of two types: one is the inhibition of the initial step of protein synthesis (I-type) and the other the inhibition of the elongation-termination step (ET-type). Nivalenol is acting on the initial step of protein synthesis with an ID50 of 2.5 mg/mL in rabbit reticulocytes . Being potent direct and indirect inhibitors of protein, deoxyribonucleic (DNA) and ribonucleic (RNA) acids synthesis, trichothecenes are especially toxic to tissues with a high cell proliferation rate.
Nivalenol rapidly inhibited protein synth both in HELA cells and in yeast spheroblasts. Nivalenol was a potent and highly selective inhibitor of polypeptide chain initiation in eukaryotes.
Deoxynivalenol (DON) and nivalenol (NIV), trichothecene mycotoxins, are secondary metabolites produced by Fusarium fungi. Trichothecene mycotoxins cause immune dysfunction, thus leading to diverse responses to infection. The present study evaluated the effect of DON and NIV on nitric oxide (NO) production by RAW264 cells stimulated with lipopolysaccharide (LPS). LPS-induced NO production was reduced in the presence of these toxins. The transcriptional activation and expression of inducible NO synthase (iNOS) by LPS were also repressed by these toxins. DON or NIV inhibited LPS-induced expression of interferon-beta (IFN-beta), which plays an indispensable role in LPS-induced iNOS expression. These results indicate that DON and NIV inhibit the LPS-induced NO and IFN-beta production, which both play an important role for host protection against invading pathogens, and suggests that the inhibition of these factors may be involved in the immunotoxic effects of these mycotoxins.

C15H20O7

312.3151

312.12

23282-20-4

Nivalenol-13C15;911392-40-0

5284433

White to off-white solid powder

1.6±0.1 g/cm3

585.1±50.0 °C at 760 mmHg

222-223ºC

221.9±23.6 °C

0.0±3.7 mmHg at 25°C

1.658

-0.75

4

7

1

22

588

8

CC1=C[C@@H]2[C@]([C@@H](C1=O)O)([C@]3([C@@H]([C@H]([C@H]([C@@]34CO4)O2)O)O)C)CO

UKOTXHQERFPCBU-XBXCNEFVSA-N

InChI=1S/C15H20O7/c1-6-3-7-14(4-16,11(20)8(6)17)13(2)10(19)9(18)12(22-7)15(13)5-21-15/h3,7,9-12,16,18-20H,4-5H2,1-2H3/t7-,9-,10-,11-,12-,13-,14-,15+/m1/s1

(1S,2R,3S,7R,9R,10R,11S,12S)-3,10,11-trihydroxy-2-(hydroxymethyl)-1,5-dimethylspiro[8-oxatricyclo[7.2.1.02,7]dodec-5-ene-12,2'-oxirane]-4-one

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~50 mg/mL (~160.09 mM)

Solubility in Formulation 1: ≥ 5 mg/mL (16.01 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 50.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 5 mg/mL (16.01 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 50.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 5 mg/mL (16.01 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 50.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)