CYP1A1 induction and CYP3A4 inhibition by the fungicide imazalil in the human intestinal Caco-2 cells—Comparison with other conazole pesticides

Sergent, Thérèse; Dupont, Isabelle; Jassogne, Coralie; Ribonnet, Laurence; Heiden, Edwige Van der; Scippo, Marie‐Louise; Müller, Marc; McAlister, Dan; Pussemier, Luc; Larondelle, Yvan; Schneider, Yves‐Jacques

doi:10.1016/j.toxlet.2008.11.009

Cited by 41 publications

(39 citation statements)

References 62 publications

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“…Chemicals in I-B include diclofop-methyl (each of the three replicates), imazalil, malathion and vinclozolin. These chemicals were most consistently active with PPAR, but also showed some activity with PXR, CAR, AhR and SR. Imazalil is an imidazole fungicide that perturbs human genes regulated by [23] and is also a activator [21]; malathion is an organophosphorus pesticide with known SR activity [24]; vinclozolin, a dicarboximide fungicide is also a known SR active [25]; and diclofop-methyl has been shown to be PPAR [26] active in rats. Group I-D only contains diethylhexylphthalate (DEHP), which is a key plastics monomer, and has been shown to activate [27], [28], and [29].…”

Section: Resultsmentioning

confidence: 99%

Using Nuclear Receptor Activity to Stratify Hepatocarcinogens

et al. 2011

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BackgroundNuclear receptors (NR) are a superfamily of ligand-activated transcription factors that control a range of cellular processes. Persistent stimulation of some NR is a non-genotoxic mechanism of rodent liver cancer with unclear relevance to humans. Here we report on a systematic analysis of new in vitro human NR activity data on 309 environmental chemicals in relationship to their liver cancer-related chronic outcomes in rodents.ResultsThe effects of 309 environmental chemicals on human constitutive androstane receptors (CAR/NR1I3), pregnane X receptor (PXR/NR1I2), aryl hydrocarbon receptor (AhR), peroxisome proliferator-activated receptors (PPAR/NR1C), liver X receptors (LXR/NR1H), retinoic X receptors (RXR/NR2B) and steroid receptors (SR/NR3) were determined using in vitro data. Hepatic histopathology, observed in rodents after two years of chronic treatment for 171 of the 309 chemicals, was summarized by a cancer lesion progression grade. Chemicals that caused proliferative liver lesions in both rat and mouse were generally more active for the human receptors, relative to the compounds that only affected one rodent species, and these changes were significant for PPAR (p0.001), PXR (p0.01) and CAR (p0.05). Though most chemicals exhibited receptor promiscuity, multivariate analysis clustered them into relatively few NR activity combinations. The human NR activity pattern of chemicals weakly associated with the severity of rodent liver cancer lesion progression (p0.05).ConclusionsThe rodent carcinogens had higher in vitro potency for human NR relative to non-carcinogens. Structurally diverse chemicals with similar NR promiscuity patterns weakly associated with the severity of rodent liver cancer progression. While these results do not prove the role of NR activation in human liver cancer, they do have implications for nuclear receptor chemical biology and provide insights into putative toxicity pathways. More importantly, these findings suggest the utility of in vitro assays for stratifying environmental contaminants based on a combination of human bioactivity and rodent toxicity.

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Section: Resultsmentioning

confidence: 99%

Using Nuclear Receptor Activity to Stratify Hepatocarcinogens

et al. 2011

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“…This antagonism suggests that, in addition to inhibiting bee P450 enzymes, the SBI fungicides may also induce P450 gene expression at low levels of exposure, including the genes encoding P450 isozymes that are involved in tau-fluvalinate detoxication [39]. Low doses of P450 inhibitors have been found to induce P450 gene expression in other insects [58] and SBI fungicides can induce P450 enzyme activity in mammals [59]. Quercetin, a pollen flavonol that is known to interact with bee P450s [60], caused a similar reduction in tau-fluvalinate toxicity in bees [61].…”

Section: Discussionmentioning

confidence: 99%

Acaricide, Fungicide and Drug Interactions in Honey Bees (Apis mellifera)

et al. 2013

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BackgroundChemical analysis shows that honey bees (Apis mellifera) and hive products contain many pesticides derived from various sources. The most abundant pesticides are acaricides applied by beekeepers to control Varroa destructor. Beekeepers also apply antimicrobial drugs to control bacterial and microsporidial diseases. Fungicides may enter the hive when applied to nearby flowering crops. Acaricides, antimicrobial drugs and fungicides are not highly toxic to bees alone, but in combination there is potential for heightened toxicity due to interactive effects.Methodology/Principal FindingsLaboratory bioassays based on mortality rates in adult worker bees demonstrated interactive effects among acaricides, as well as between acaricides and antimicrobial drugs and between acaricides and fungicides. Toxicity of the acaricide tau-fluvalinate increased in combination with other acaricides and most other compounds tested (15 of 17) while amitraz toxicity was mostly unchanged (1 of 15). The sterol biosynthesis inhibiting (SBI) fungicide prochloraz elevated the toxicity of the acaricides tau-fluvalinate, coumaphos and fenpyroximate, likely through inhibition of detoxicative cytochrome P450 monooxygenase activity. Four other SBI fungicides increased the toxicity of tau-fluvalinate in a dose-dependent manner, although possible evidence of P450 induction was observed at the lowest fungicide doses. Non-transitive interactions between some acaricides were observed. Sublethal amitraz pre-treatment increased the toxicity of the three P450-detoxified acaricides, but amitraz toxicity was not changed by sublethal treatment with the same three acaricides. A two-fold change in the toxicity of tau-fluvalinate was observed between years, suggesting a possible change in the genetic composition of the bees tested.Conclusions/SignificanceInteractions with acaricides in honey bees are similar to drug interactions in other animals in that P450-mediated detoxication appears to play an important role. Evidence of non-transivity, year-to-year variation and induction of detoxication enzymes indicates that pesticide interactions in bees may be as complex as drug interactions in mammals.

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“…An increasing number of studies demonstrate that intestinal epithelial cells are targets for food contaminants, including mycotoxins [129,130,131]. …”

Section: Discussionmentioning

confidence: 99%

Effect of Deoxynivalenol and Other Type B Trichothecenes on the Intestine: A Review

Pinton

Oswald

2014

Toxins

291

240

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The natural food contaminants, mycotoxins, are regarded as an important risk factor for human and animal health, as up to 25% of the world’s crop production may be contaminated. The Fusarium genus produces large quantities of fusariotoxins, among which the trichothecenes are considered as a ubiquitous problem worldwide. The gastrointestinal tract is the first physiological barrier against food contaminants, as well as the first target for these toxicants. An increasing number of studies suggest that intestinal epithelial cells are targets for deoxynivalenol (DON) and other Type B trichothecenes (TCTB). In humans, various adverse digestive symptoms are observed on acute exposure, and in animals, these toxins induce pathological lesions, including necrosis of the intestinal epithelium. They affect the integrity of the intestinal epithelium through alterations in cell morphology and differentiation and in the barrier function. Moreover, DON and TCTB modulate the activity of intestinal epithelium in its role in immune responsiveness. TCTB affect cytokine production by intestinal or immune cells and are supposed to interfere with the cross-talk between epithelial cells and other intestinal immune cells. This review summarizes our current knowledge of the effects of DON and other TCTB on the intestine.

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CYP1A1 induction and CYP3A4 inhibition by the fungicide imazalil in the human intestinal Caco-2 cells—Comparison with other conazole pesticides

Cited by 41 publications

References 62 publications

Using Nuclear Receptor Activity to Stratify Hepatocarcinogens

Using Nuclear Receptor Activity to Stratify Hepatocarcinogens

Acaricide, Fungicide and Drug Interactions in Honey Bees (Apis mellifera)

Effect of Deoxynivalenol and Other Type B Trichothecenes on the Intestine: A Review

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