Highlight report: hepatotoxicity of triazole fungicides

Albrecht, Wiebke

doi:10.1007/s00204-019-02555-x

Cited by 8 publications

(2 citation statements)

References 20 publications

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“…In search of new potent inhibitors with selectivity to individual CDKs, we took advantage of the structure of PHA-793887 for the design of imidazole-4-N-acetamide-based CDK inhibitors [10]. Triazol-and pyrazol-containing compounds are known to evoke liver toxicity [11,12]. Furthermore, the pyrazole cycle was shown to mediate oxidative liver injury [13,14].…”

Section: Introductionmentioning

confidence: 99%

Imidazole-4-N-acetamide Derivatives as a Novel Scaffold for Selective Targeting of Cyclin Dependent Kinases

Rusina,

Gandalipov,

Abdusheva

et al. 2023

Cancers

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The rational design of cyclin-dependent protein kinase (CDK) inhibitors presumes the development of approaches for accurate prediction of selectivity and the activity of small molecular weight anticancer drug candidates. Aiming at attenuation of general toxicity of low selectivity compounds, we herein explored the new chemotype of imidazole-4-N-acetamide substituted derivatives of the pan-CDK inhibitor PHA-793887. Newly synthesized compounds 1–4 containing an aliphatic methyl group or aromatic radicals at the periphery of the scaffold were analyzed for the prediction of relative free energies of binding to CDK1, -2, -5, and -9 using a protocol based on non-equilibrium (NEQ) thermodynamics. This methodology allows for the demonstration of a good correlation between the calculated parameters of interaction of 1–4 with individual targets and the values of inhibitory potencies in in vitro kinase assays. We provide evidence in support of NEQ thermodynamics as a time sparing, precise, and productive approach for generating chemical inhibitors of clinically relevant anticancer targets.

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Section: Introductionmentioning

confidence: 99%

Imidazole-4-N-acetamide Derivatives as a Novel Scaffold for Selective Targeting of Cyclin Dependent Kinases

Rusina,

Gandalipov,

Abdusheva

et al. 2023

Cancers

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“…The blocking of sterol 14α demethylase results in a deficiency of ergosterol, which is essential for cell membranes in yeast and fungi [6][7][8]. It has been shown that fungicides have toxic effects on mammal organisms [9][10][11] and numerous studies have revealed that EPX produced brain, cardiac, liver, kidney, intestinal, and endocrine-disrupting toxicity [12][13][14][15][16][17]. There have been few studies on metabolic toxicity and intestinal barrier function impairment in mice.…”

Section: Introductionmentioning

confidence: 99%

Oral Exposure to Epoxiconazole Disturbed the Gut Micro-Environment and Metabolic Profiling in Male Mice

Weng

Wang

et al. 2023

Metabolites

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Epoxiconazole (EPX), a triazole fungicide, is widely used in agriculture to control pests and diseases. High residual and occupational exposure to EPX increases health risks, and evidence of potential harm to mammals remains to be added. In the present study, 6-week-old male mice were exposed to 10 and 50 mg/kg bw EPX for 28 days. The results showed that EPX significantly increased the liver weights. EPX also decreased the mucus secretion of the colon and altered intestinal barrier function in mice including a reduced expression of some genes (Muc2, meprinβ, tjp1). Moreover, EPX altered the composition and abundance of gut microbiota in the colon of mice. The alpha diversity indices (Shannon, Simpson) in the gut microbiota increased after exposure to EPX for 28 days. Interestingly, EPX increased the ratio of Firmicutes to Bacteroides and the abundance of other harmful bacteria including Helicobacter and Alistipes. Based on the untargeted metabolomic analysis, it was found that EPX altered the metabolic profiles of the liver in mice. KEGG analysis of differential metabolites revealed that EPX disrupted the pathway related to glycolipid metabolism, and the mRNA levels of related genes were also confirmed. In addition, the correlation analysis showed that the most altered harmful bacteria were associated with some significantly altered metabolites. The findings highlight that EPX exposure changed the micro-environment and lipid metabolism disturbance. These results also suggest that the potential toxicity of triazole fungicides to mammals cannot be ignored.

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Agricultural Triazole Fungicides

Henriquez,

Domoradzki,

Yan

et al. 2023

Patty's Toxicology

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Microbial diseases account for 16% of crop losses annually with fungal pests accounting for approximately 80% of that loss. Several classes of molecules have been used as fungicides for agricultural purposes. Triazole fungicides were first introduced in the mid‐1970, and they are highly effective against powdery mildews, rusts, and leaf‐spotting fungi. Currently, there are 26 commercially available triazole fungicides, with 19 having registration for agricultural use in the United States and the European Union for a variety of crops. Despite their general acceptance, triazole fungicides face regulatory hurdles due to toxicological concerns for endocrine disruption, developmental and reproductive toxicity, and liver toxicity. Further, increasing incidence of triazole resistance and changes in global weather patterns is warranting increased application rates to protect significant food crops from fungal pests. All these pressures pose challenges to farmers, agrochemical companies, and regulatory agencies which need to keep these important agricultural tools in the field while assuring safety to applicators, consumers, and the environment.

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Highlight report: hepatotoxicity of triazole fungicides

Cited by 8 publications

References 20 publications

Imidazole-4-N-acetamide Derivatives as a Novel Scaffold for Selective Targeting of Cyclin Dependent Kinases

Imidazole-4-N-acetamide Derivatives as a Novel Scaffold for Selective Targeting of Cyclin Dependent Kinases

Oral Exposure to Epoxiconazole Disturbed the Gut Micro-Environment and Metabolic Profiling in Male Mice

Agricultural Triazole Fungicides

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