Metabolism of 4-methylimidazole in Fischer 344 rats and B6C3F1 mice

Fennell, Timothy R.; Watson, Scott L.; Dhungana, Suraj; Snyder, Rodney W.

doi:10.1016/j.fct.2018.10.032

Cited by 12 publications

(10 citation statements)

References 36 publications

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“…Foi encontrado um pequeno aumento de marcadores BrdU entre camundongos machos expostos a 1,25 mg/g de 4-MEI, não apresentando diferença estatisticamente significativa, em comparação com o aumento de 27 vezes produzido pelo estireno. Fennell et al (2019) investigaram o metabolismo in vitro em ratos e camundongos, comparado com o metabolismo in vivo. Foram administrados 50 e 150 mg/kg p.c.…”

Section: Resultsunclassified

O subproduto do corante caramelo IV em alimentos pode causar toxicidade?

Gomes

Souza

Menezes

2021

RSD

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O corante caramelo tem sido amplamente utilizado em alimentos e bebidas e é regulamentado globalmente como aditivo químico. As quatro classes distintas do corante caramelo (caramelo simples (I), caramelo sulfito (II), caramelo de amônia (III) e caramelo sulfito-amônia (IV)) são bem caracterizadas e cada uma tem especificidades que variam com os tipos de processamento do composto, especialmente a adição de reagentes que podem dar origem a compostos de baixo peso molecular, como por exemplo, o 4-metilimidazol, subproduto do caramelo IV, que pode ter significativo efeito toxicológico. Tendo em vista o elevado consumo de alimentos industrializados e a potencial exposição em longo prazo desse composto, em diferentes faixas etárias, o objetivo desta revisão foi resumir os estudos mais relevantes disponíveis nos últimos 5 anos sobre os efeitos tóxicos do 4-metilimidazol, nas bases de dados PubMed, Science Direct e Lilacs. Os resultados dos estudos avaliados são divergentes e os mecanismos de toxicidade ainda não estão bem elucidados, apesar de alguns estudos terem encontrado efeitos negativos à saúde com a exposição ao 4-metilimidazol, tornando-se relevante novos estudos para esclarecer a sua real segurança.

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Section: Resultsunclassified

O subproduto do corante caramelo IV em alimentos pode causar toxicidade?

Gomes

Souza

Menezes

2021

RSD

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“…Similar metabolites were detected by LC-MS in mouse urine: 4hydroxymethylimidazole (2.4-4.8%), a mono-glucuronide conjugate, 4-hydroxymethylimidazole glucuronide (3.8-6.6%) and 5-methylhydantoin (16.7-20.9%) at the 50 mg/kg-bw dose. Thus, 4-MeI metabolism appeared to occur through similar pathways in rats and mice (Fennell et al 2019).…”

Section: Introductionmentioning

confidence: 87%

“…Chemical abstract services registry numbers (CASRNs), chemical names, simplified molecular-input line-entry system (SMILES) strings and chemical structures, obtained from the study of Fennell et al (2019) and confirmed in ChemIDPlus, of the compounds of interest are shown in Table 1.…”

Section: Chemicals and Structuresmentioning

confidence: 99%

“…Structure-activity relationship (SAR) studies have been increasingly used to identify molecular features that are associated with a variety of toxic endpoints, including carcinogenicity and genotoxicity. To further understand the mode of action associated with induction of mouse lung tumor formation following chronic exposure to high concentrations of 4-MeI in the diet, two SAR programs were utilized to identify potential carcinogenic and/or genotoxic structural alerts and features present in 4-MeI and metabolites identified by Fennell et al (2019). Structural features combined with the available literature for the compounds of interest, were used to draw conclusions regarding the strength of the predictions observed using carcinogenicity and genotoxicity SAR models.…”

Section: Introductionmentioning

confidence: 99%

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Evaluation of two in silico programs for predicting mutagenicity and carcinogenicity potential for 4-methylimidazole (4-MeI) and known metabolites

Howard

Choksi

2020

Toxicology Mechanisms and Methods

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4-Methylimidazole (4-MeI) is a nitrogen-containing heterocyclic compound that is used in the manufacture of chemicals, dyes and pharmaceuticals and may be found in a variety of foods following formation during heating. The purpose of this study was to use two different in silico programs, CASE Ultra and Toxtree, to investigate potential structure-activity relationships in 4-MeI and its metabolites for mutagenicity and carcinogenicity, and combine that information with the available literature to draw conclusions regarding the strength of the predictions observed. Neither CASE Ultra nor Toxtree identified any structural alerts that were associated with mutagenic activity. Data for 4-MeI from a single study were used in the development of the CASE Ultra mouse and rat carcinogenicity models, but no additional similar structures were identified in the carcinogenicity model training set. One metabolite, 5-methylhydantoin, was predicted to be positive in the CASE Ultra carcinogenicity male and female mouse models; positive predictivity percentages of 60.9% and 73.7%, respectively. However, low structural similarity between 5-methylhydantoin and the compounds identified in the training set (<25%) decreases confidence in the positive prediction. Three metabolites were predicted to be positive in the CASE Ultra mouse micronucleus model, but again suffered from low structural similarity. Both limited structural similarity and inconsistent responses among the other clastogenicity models suggest that additional structurally similar compounds are needed to assess the predictive capacity of these alerts for biological activity of these compounds.

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“…Abundant distribution throughout the airway tree makes mice an ideal model to study Club cell toxicity, while human Club cells are more restricted to distal airways. 4MEI metabolism was demonstrated in mice and rats (22 to 40% of 50 or 150mg/kg oral gavage 14 C 4MEI) (Fennell et al, 2019)), goats (85% of the 20 mg/kg orally administered and 80% of the 20 mg/kg intravenous 4MEI) (Nielsen et al, 1993), and in heifers (25% of 20 mg/kg intravenous 4MEI) (Nielsen et al, 1993). Comparison of pulmonary injury after chronic 4MEI dietary exposure and intraperitoneal injection of the known Club cell toxicant, styrene, did not identify a cellular target for 4MEI toxicity (Cruzan et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Comparison of acute respiratory epithelial toxicity for 4-Methylimidazole and naphthalene administered by oral gavage in B6C3F1 mice

Kelty

Keum

Brown

et al. 2020

Regulatory Toxicology and Pharmacology

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4-Methylimidazole (4MEI) 1 is a contaminant in food and consumer products. Pulmonary toxicity and carcinogenicity following chronic dietary exposures to 4MEI is a regulatory concern based on previous rodent studies. This study examined acute pulmonary toxicity in B6C3F1 mice from 6 hours to 5 days after oral gavage with a single dose of 150 mg/kg 4MEI, a double dose delivered 6 hours apart, or vehicle controls. Oral gavage of 150 mg/kg naphthalene, a prototypical Club cell toxicant, was used as a positive control. Intrapulmonary conducting airway cytotoxicity was assessed in fixed-pressure inflated lungs using qualitative histopathology scoring, quantitative morphometric measurement of vacuolated and exfoliating epithelial cells, and immunohistochemistry. 4MEI treatment did not change markers of cytotoxicity including the mass of vacuolated epithelium, the thickness of the epithelium, or the distributions of epithelial proteins: secretoglobin 1A1, proliferating cell nuclear antigen, calcitonin gene-related peptide, and myeloperoxidase. 4MEI and vehicle controls caused slight cytotoxicity with rare vacuolization of the epithelium relative to the severe bronchiolar epithelial cell toxicity found in the naphthalene exposed mice at terminal bronchioles, intrapulmonary airways, or airway bifurcations. In summary, 4MEI caused minimal airway epithelial toxicity without characteristic Club Cell toxicity when compared to naphthalene, a canonical Club Cell toxicant.

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Metabolism of 4-methylimidazole in Fischer 344 rats and B6C3F1 mice

Cited by 12 publications

References 36 publications

O subproduto do corante caramelo IV em alimentos pode causar toxicidade?

O subproduto do corante caramelo IV em alimentos pode causar toxicidade?

Evaluation of two in silico programs for predicting mutagenicity and carcinogenicity potential for 4-methylimidazole (4-MeI) and known metabolites

Comparison of acute respiratory epithelial toxicity for 4-Methylimidazole and naphthalene administered by oral gavage in B6C3F1 mice

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