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Background: 4-Methylimidazole (4-MeI) or 4-methyl-1H-imidazole, a slightly yellowish solid with molecular formula C4H6N2, is a heterocyclic compound which supposedly does not exist as a natural product and is formed when carbohydrates are heating with ammonium compounds. This compound is used in pharmaceuticals, agriculture and photography chemicals, dyes and pigments, and rubber manufacturing. In the present study, a simple and efficient sample preparation method designated gas flow headspace liquid phase microextraction (GF-HS-SDME) was employed for the extraction and preconcentration of 4-methylimidazole (4-MeI) from food and beverage samples, before its determination by gas chromatography-mass spectrometry. Result: To investigate the optimal conditions for the extraction process in GF-HS-SDME method, factors affecting extraction, including selection of extraction solvent, vial volume, extraction solvent ratio, position of extracting solvent, drop volume, sample volume, stirring speed, temperature, extraction time, sample pH, ionic strength of the sample solution and gas flow rate were optimized by utilizing both one-variable-at-a-time method and Plackett–Burman design. The investigation of protocol was carried out by using a standard solution containing 100.0 μg L−1 of 4-MeI in deionized water. Conclusion: In this study, a simple and green analytical method based on GF-HS-SDME was proposed for the extraction and preconcentration of 4-MeI from foodstuffs, followed by GC–MS determination. The main advantage of this method is its high preconcentration factor and fastness due to the application of an inert gas stream during microextraction. [ABSTRACT FROM AUTHOR]

4-methylimidazole (4-MEI), is received to humans through the foods and other sources. We have investigated neurobehavioral and developmental toxicity of 4-MEI in mother and offspring in mice. Results in vivo, showed that 4-MEI (100, 200 and 300 mg/kg) can induce neurobehavioral toxicity in pregnant mice by abnormalities in the hippocampus and disrupt neurobehavioral functions. Observation on fetuses showed that 4-MEI induces abortion, decrease the weight and length of the fetus and pathological abnormalities. These results suggested 4-MEI induces neurobehavioral and developmental toxicity. It is hoped that these results will be helpful for awareness of humans which are exposed with 4-MEI. [ABSTRACT FROM AUTHOR]

Abstract: 4-Methylimidazole (4-MEI) is found in a wide array of food products. The National Toxicology Program (NTP) recently conducted a two-year feeding cancer bioassay of 4-MEI in B6C3F1 mice and F344/N rats. In rats, NTP found “equivocal evidence of carcinogenic activity” in females based on increased incidences of mononuclear cell leukemia and “no evidence of carcinogenic activity” in males. However, dose-related, statistically significant decreases in multiple tumors were observed in both male and female rats exposed to 4-MEI in the NTP bioassay. For example, 4-MEI was associated with a 25-fold decrease in the incidence of mammary tumors among high dose females. NTP noted briefly that the decreases in certain tumors, including mammary tumors, were greater than could be attributed to body weight alone. The present paper provides a more detailed evaluation of the evidence that 4-MEI exhibits tumor preventive activity in the rat based upon the results of the NTP bioassay. Reduced body weight offers a partial explanation for the reduction in tumors, but does not appear to be the primary cause of the decreased tumor incidences, indicating that 4-MEI itself may possess an ability to prevent tumor formation. [Copyright &y& Elsevier]

A sensitive method using ion-pair extraction was developed by liquid chromatography tandem mass spectrometry (LC-MS/MS) for measurement of 4-methylimidazole (4-MI) in NMRI mice plasma and cerebrospinal fluid (CSF). Detection was done by electrospray positive ionization mass spectrometry in the multiple-reaction monitoring (MRM) mode. The validation method was applied to quantification of 4-MI in plasma and CSF samples using oral doses of 100, 200, and 300 mg/kg in NMRI mice. The efficiency of the method was evaluated in terms of linearity (R 2 > 0.99), recovery (98-107%, 3 levels) and precision (8-10%, 3 levels, n = 6). Limit of detection (LOD) and limit of quantification (LOQ) were 25 ng/mL and 50 ng/mL, respectively. The results obtained showed that the exposure to oral doses of 4-MI in mice makes different concentrations in plasma and CSF and causes significant changes in mice. This study was the first report for determination of 4-MI in plasma and CSF samples in mice. Our results suggest that LC-MS/MS-based on ion-pair extraction is a robust method with high detection ability for measurement of 4-MI in plasma and CSF samples. Therefore, the developed method can be useful for evaluation and monitoring of imidazole derivatives in biological samples. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

A series of manganese(III) porphyrins with 4-methylimidazole have been prepared. These are high-spin complexes having general formula [MnIII(THMPP)X(4-MeIm)], where THMP = 5,10,15,20-tetra(4-hydroxy-3-methoxyphenyl)porphine ligand, X = Cl−, Br−, NCS−, or N3− and 4-MeIm = 4-methylimidazole. All the complexes have been characterized by UV-visible, FT-IR, ESI-MS spectra, elemental analyses and magnetic susceptibility measurements. These manganese(III) porphyrins oxidize aromatic alcohols to aldehydes. The oxidation reactions have been carried out at room temperature in the presence of oxidants such as NaIO4, H2O2, and NaOCl. The comparative studies proved that NaIO4 behaves as the most efficient oxidant in these oxidative transformation reactions. [ABSTRACT FROM AUTHOR]

On the basis of magnetic molecularly imprinted polymer (MMIP) solid-phase extraction coupled with high performance liquid chromatography, we established a new method for the determination of the 4-methylimidazole (4-MEI) in soy sauce. Scanning electron microscopy (SEM), Fourier transform infrared (FT-IR), X-ray diffraction (XRD) and vibrating sample magnetometer (VSM) were used to characterize the synthesized MMIPs. To evaluate the polymers, batch rebinding experiments were carried out. The binding strength and capacity were determined from the derived Freundlich isotherm (FI) equation. The selective recognition capability of MMIPs was investigated with a reference compound and a structurally similar compound. As a selective pre-concentration sorbents for 4-methylimidazole in soy sauce, the MMIPs showed a satisfied recoveries rate of spiked samples, ranged from 97% to 105%. As a result, the prepared MMIPs could be applied to selectively pre-concentrate and determine 4-methylimidazole in soy sauce samples. [ABSTRACT FROM AUTHOR]

A survey of 2-acetyl-4-tetrahydroxybutylimidazole (THI) and 4-methylimidazole (4-MeI) concentrations in caramel colours, vinegar and beverages from the Chinese market were performed by ultrahigh-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). In total, 117 samples, 78 caramel colour samples, 23 vinegar samples and 16 beverage samples, were investigated. The results indicated that 4-MeI was found in all samples. THI was found in a part of the samples and also the level range was lower compared to 4-MeI. In caramel colour samples, the concentration level range of THI was 1.0–74.3 mg/kg and of 4-MeI was 1.5–1291.8 mg/kg. In vinegar samples, the concentration level range of THI was 13.3–119.2 µg/L and for 4-MeI 111.2–2077.8 µg/L. In beverage samples, THI was only found in two samples and the concentration level range of 4-MeI was 10.8–307.1 µg/L. THI and 4-MeI levels in vinegar and beverages were rather low compared with those in caramel colour samples. These observations can be helpful for evaluating individual exposure to THI and 4-MeI from caramel colours, vinegar and beverages in China. [ABSTRACT FROM AUTHOR]

2- and 4-methylimidazoles (2-MI and 4-MI) are undesired byproducts produced during the manufacture of caramel color used to darken food products such as carbonated beverages. The Office of Environmental Health Hazard Assessment in California listed 4-MI as carcinogen in January 2011 with a proposed no significant risk level at 29 μg per person per day. Thus, a quantitative analytical measurement for 2-MI and 4-MI is desired for reliable risk assessments for exposure. An ultra-performance liquid chromatography (UPLC) coupled tandem mass spectrometric (MS/MS) method was developed for the quantification of 4-MI in beverage samples. Chromatographic separation of 2-MI and 4-MI were achieved by using a PFP reversed-phase column and a stepwise gradient of methanol and distilled water containing 0.1 % formic acid. Identification and quantification of 2-MI and 4-MI were performed using electrospray ionization-tandem mass monitoring the precursor to product ion transitions for 2-MI at m/ z 83.1 → 42.2 and 4-MI at m/ z 83.1 → 56.1 with melamine at m/ z 127.1 → 85.1 as the internal standard. The performance of the method was evaluated against validation parameters such as specificity, carryover, linearity and calibration, correlation of determination (r), detection limit, precision, accuracy, and recovery. Calibration curves at 10-400 ng/mL were constructed by plotting concentration versus peak-area ratio (analyte/internal standard) and fitting the data with a weighted 1/x. The accuracy of the assay ranged from 93.58 to 110.53 % for all analytes. Intra-assay precision for 2-MI and 4-MI were below 7.28 (relative standard deviation/RSD %) at QC samples. Here we present a new and improved method using UPLC-MS/MS to significantly simplify sample preparation and decrease chromatographic run time. This method allows accurate and reproducible quantification of 4-MI in carbonated beverages as low as sub ng/mL (ppb) levels. [ABSTRACT FROM AUTHOR]

A simple method to detect 4-methylimidazole in soft drinks is described. This method is based on headspace solid-phase micro-extraction and gas chromatography-mass spectrometry (HS-SPME GC-MS). The HS-SPME parameters (selection of fiber, extraction temperature, heating time, and pH) were optimized and selected. Under the established condition, the detection and the quantification limit were 1.9 and 6.0 μg L using 4 mL of the liquid sample, respectively. The relative standard deviation for five independent determinations at 100.0 and 500.0 μg L was less than 8 %. The calibration curve was y = 0.6027 x-0.0033 with a linearity of r = 0.997. Using the proposed method, the levels of 4-MEI were detected in a range from 94.0 to 324.8 μg L. The comparison of liquid chromatography tandem mass spectrometry (LC-MS/MS) with the proposed method was performed and the agreement with LC-MS/MS for all samples was acceptable. [ABSTRACT FROM AUTHOR]

4-Methylimidazole (4MeI) is a tremorogenic and convulsive agent of concern both in human and veterinary toxicology. The in vitro effects of 4MeI (5 μM–20 mM) on cerebral glutamate decarboxylase (GAD) activity and (in concentrations up to 50 mM) on binding of [3H]GABA to cerebral GABA receptors were tested in brain tissue from B6D2 mice. The effects of 1-methylimidazole (1MeI), 2-methylimidazole (2MeI), 4-methylhydroxy-imidazole (4MeOHI), imidazole-4-acetic acid (4AcI) (all in concentrations of 5–20 mM) and imidazole (20 mM) on GAD activity were also tested. In addition, the effect of a lethal dose of 4MeI (250 mg/kg ip) to B6D2 mice in vivo on the postmortem concentrations of γ-aminobutyric acid (GABA) and glutamate in their brains were measured. In all experiments, student’s t-test was used for statistical comparison. 4MeI in concentrations of 2 mM and above did inhibit GAD activity significantly in vitro, but glutamate and GABA concentrations in mouse brains after lethal 4MeI poisoning were not significantly different from control values. The effect of 2MeI on GAD activity was stronger than the effect of 4MeI. Binding of [3H]GABA to cerebral GABA receptors in vitro was significantly inhibited only at 4MeI concentrations of 5 mM and above. The results indicate that neither inhibition of GABA synthesis nor competitive inhibition of the binding of GABA to its receptors are likely mechanisms for the excitation and convulsions seen in 4MeI poisoning in animals. [ABSTRACT FROM AUTHOR]

4-Methylimidazole (4MI) is used in the manufacture of pharmaceuticals, photographic chemicals, dyes and pigments, cleaning and agricultural chemicals, and rubber. It has been identified as a by-product of fermentation in foods and has been detected in mainstream and side stream tobacco smoke. 4MI was studied because of its high potential for human exposure. Groups of 50 male and 50 female F344/N rats were fed diets containing 0-, 625-, 1,250-, or 2,500 ppm 4MI (males) or 0-, 1,250-, 2,500-, or 5,000 ppm 4MI (females) for 106 weeks. Based on the food consumption the calculated average daily doses were approximately 30, 55, or 115 mg 4MI/kg body weight to males and 60, 120, or 250 mg 4MI/kg to females. Survival of all exposed groups of males and females was similar to that of the control groups. The mean body weights of males in the 1,250- and 2,500 ppm groups and females in the 2,500- and 5,000 ppm groups were less than those of the control groups throughout the study. Feed consumption by 5,000 ppm females was less than that by the controls. Clonic seizures, excitability, hyperactivity, and impaired gait were observed primarily in 2,500- and 5,000 ppm females. The incidence of mononuclear cell leukemia in the 5,000 ppm females was significantly greater than that in the controls. The incidences of hepatic histiocytosis, chronic inflammation, and focal fatty change were significantly increased in all exposed groups of male and female rats. The incidences of hepatocellular eosinophilic and mixed cell foci were significantly increased in 2,500 ppm males and 5,000 ppm females. Groups of 50 male and 50 female B6C3F1 mice were fed diets containing 0-, 312-, 625-, or 1,250 ppm 4MI for 106 weeks. Based on the food consumption the calculated average daily doses were approximately 40, 80, or 170 mg 4MI/kg body weight to males and females. Survival of all exposed groups of males and females was similar to that of the control groups. Mean body weights of males and females in the 1,250 ppm groups and that in the 312- and 625 ppm females were less than those of the control groups. Feed consumption by exposed groups of male and female mice was similar to that by the controls. The incidences of alveolar/bronchiolar adenoma in all exposed groups of females, alveolar/bronchiolar carcinoma in 1,250 ppm males, and alveolar/bronchiolar adenoma or carcinoma (combined) in 1,250 ppm males and 625- and 1,250 ppm females were significantly greater than those in the control groups. The incidence of alveolar epithelial hyperplasia was significantly increased in the 1,250 ppm females. 4MI is carcinogenic inducing alveolar/bronchiolar adenoma and carcinoma in male and female mice. 4MI may also induce mononuclear cell leukemia in female rats. [ABSTRACT FROM AUTHOR]

2-Methylimidazole (2-MI) and 4-methylimidazole (4-MI) can be formed via the Maillard reaction during dairy thermal treatment. In this study, different reactions between α-dicarbonyl compounds (methylglyoxal, glyoxal) and aldehydes (formaldehyde, acetaldehyde) in the presence of ammonium sulfate were performed to investigate the formation of 2-MI and 4-MI. Two formation pathways of 2-MI and 4-MI were proposed. One pathway is that α-dicarbonyl compound reacts with equivalent ammonia to form an intermediate, while aldehyde reacts with equivalent ammonia to form another intermediate, then the 2 intermediates react together to generate 2-MI or 4-MI. Alternatively, α-dicarbonyl compound can react with double ammonia to form an intermediate, and subsequently reacts with aldehyde to form 2-MI or 4-MI. Additionally, possible mechanisms were also proposed to explain the phenomenon that the 2-MI content was much lower than 4-MI in Maillard reaction. [ABSTRACT FROM AUTHOR]

A method for simultaneous determination of 4-methylimidazole (4-MeI), 2-methylimidazole (2-MeI) and 5-hydroxymethylfurfural (HMF) in beverages was developed using solid-phase extraction (SPE) and amino trap column coupled with pulsed amperometric detection (AMTC-PAD). A single amino trap column (P/N: 046122) was first applied to separate the targeted analytes in samples after SPE pretreatment. This method demonstrated low limit of quantification (0.030 mg/L for methylimidazoles and 0.300 mg/L for HMF) and excellent linearity with correlation of determination ( R 2 = 0.999 for 2-MeI, 0.997 for 4-MeI and 0.998 for HMF). Nearly no 2-MeI was found in all soft drinks. However, 4-MeI could be detected in cola drinks and soft drinks containing caramel colour (ranging from 0.13 to 0.34 mg/L), whereas HMF were only found in cola drinks (ranging from 1.07 to 4.47 mg/L). Thus, AMTC-PAD technique would be a valid and inexpensive alternative to analysis of 4-MeI, 2-MeI and HMF. [ABSTRACT FROM AUTHOR]

A simultaneous analysis of methylimidazoles, reducing sugars, and 5-hydroxymethyl-2-furaldehyde in the Maillard reaction was improved by use of an amino trap column. Analysis was carried out by using high- performance anion exchange chromatography with pulsed amperometric detection (HPAEC-PAD) coupled with an amino trap column. The amino trap column was a useful tool to improve the separation of methylimidazoles, reducing sugars, and 5-hydroxymethyl-2-furaldehyde. This technique is useful for simultaneous analysis of methylimidazoles, reducing sugars, and 5-hydroxymethyl-2-furaldehyde in risk assessment for dairy products. [ABSTRACT FROM AUTHOR]