2-아미노-3,8-디메틸이미다조(4,5-F)퀴녹사린

log Kow = 1.01

1.01

Yellow solid; [Toronto Research Chemicals MSDS]

Solid

Warning

H351 (100%): Suspected of causing cancer [Warning Carcinogenicity]

P203, P280, P318, P405, and P501 (click each P-code to see the statement)

The GHS information provided by 1 company from 1 notification to the ECHA C&L Inventory.

IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. MeIQx in: Some Naturally Occurring Substances: Food Items and Constituents, Heterocyclic Aromatic Amines and Mycotoxins (vol 56). p.210-228. (1993). IARC Monographs provide critical reviews of data on carcinogenicity for agents to which humans are known to be exposed and on specific exposure situations.[Available from, as of November 18, 2009: http://monographs.iarc.fr/ENG/Monographs/vol56/mono56-12.pdf]

National Toxicology Program. Eleventh Report on Carcinogens (2005). The Report on Carcinogens is an informational scientific and public health document that identifies and discusses substances (including agents, mixtures, or exposure circumstances) that may pose a carcinogenic hazard to human health. 2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) (77500-04-0) is listed as reasonably anticipated to be a human carcinogen.[Available from, as of September 23, 2009: http://ntp.niehs.nih.gov/ntp/roc/eleventh/profiles/s092vhca.pdf]

PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following procedure must be adopted. The carcinogen should be enclosed in a securely sealed, watertight container (primary container), which should be enclosed in a second, unbreakable, leakproof container that will withstand chem attack from the carcinogen (secondary container). The space between primary & secondary container should be filled with absorbent material, which would withstand chem attack from the carcinogen & is sufficient to absorb the entire contents of the primary container in the event of breakage or leakage. Each secondary container should then be enclosed in a strong outer box. The space between the secondary container & the outer box should be filled with an appropriate quantity of shock-absorbent material. Sender should use fastest & most secure form of transport & notify recipient of its departure. If parcel is not received when expected, carrier should be informed so that immediate effort can be made to find it. Traffic schedules should be consulted to avoid ... arrival on weekend or holiday ... /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should be avoided. To avoid spilling, carcinogens should be transported in securely sealed glass bottles or ampoules, which should themselves be placed inside strong screw-cap or snap-top container that will not open when dropped & will resist attack from the carcinogen. Both bottle & the outside container should be appropriately labelled. ... National post offices, railway companies, road haulage companies & airlines have regulations governing transport of hazardous materials. These authorities should be consulted before ... material is shipped. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practical to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen & date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured & the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed & labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": Carcinogens that are alkylating, arylating or acylating agents per se can be destroyed by reaction with appropriate nucleophiles, such as water, hydroxyl ions, ammonia, thiols & thiosulfate. The reactivity of various alkylating agents varies greatly ... & is also influenced by sol of agent in the reaction medium. To facilitate the complete reaction, it is suggested that the agents be dissolved in ethanol or similar solvents. ... No method should be applied ... until it has been thoroughly tested for its effectiveness & safety on material to be inactivated. For example, in case of destruction of alkylating agents, it is possible to detect residual compounds by reaction with 4(4-nitrobenzyl)-pyridine. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": ... Small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as saturated soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp & carcinogenic wastes generated by this treatment conducted to & burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter & misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous & organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/

For more Disposal Methods (Complete) data for 2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline (6 total), please visit the HSDB record page.

PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens are used ... should be marked distinctively with appropriate labels. Access ... limited to persons involved in expt. ... A prominently displayed notice should give the name of the Scientific Investigator or other person who can advise in an emergency & who can inform others (such as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has occurred, such as spillage, should be decontaminated by lab personnel engaged in expt. Design of expt should ... avoid contamination of permanent equipment. ... Procedures should ensure that maintenance workers are not exposed to carcinogens. ... Particular care should be taken to avoid contamination of drains or ventilation ducts. In cleaning labs, procedures should be used which do not produce aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with high-efficiency particulate filter on exhaust, which are avail commercially, should be used. Sweeping, brushing & use of dry dusters or mops should be prohibited. Grossly contaminated cleaning materials should not be re-used ... If gowns or towels are contaminated, they should not be sent to laundry, but ... decontaminated or burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab could build up during conduct of expt, periodic checks should be carried out on lab atmospheres, surfaces, such as walls, floors & benches, & ... interior of fume hoods & airducts. As well as regular monitoring, check must be carried out after cleaning-up of spillage. Sensitive methods are required when testing lab atmospheres. ... Methods ... should ... where possible, be simple & sensitive. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin, animals should be kept in cages with solid bottoms & sides & fitted with a filter top. When volatile carcinogens are given, filter tops should not be used. Cages which have been used to house animals that received carcinogens should be decontaminated. Cage-cleaning facilities should be installed in area in which carcinogens are being used, to avoid moving of ... contaminated /cages/. It is difficult to ensure that cages are decontaminated, & monitoring methods are necessary. Situations may exist in which the use of disposable cages should be recommended, depending on type & amt of carcinogen & efficiency with which it can be removed. /Chemical Carcinogens/

For more Preventive Measures (Complete) data for 2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline (9 total), please visit the HSDB record page.

PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece & close-fitting at ankles & wrists), gloves, hair covering & overshoes. ... In chemical laboratory, gloves & gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, & disposable plastic aprons might provide addnl protection. ... Gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/

/It was/ previously demonstrated using a bacterial system that the antigenotoxic activity of the anthraquinone compounds purpurin and alizarin was due to the suppression of microsomal enzyme activity involved in the activation of mutagens. In the present study we determined the effect of purpurin and alizarin on (i) MeIQx-DNA-adduct formation in mouse tissues and (ii) the activity of phases I and II enzymes in liver fractions, the liver being the target tissue of MeIQx. The amount of MeIQx-DNA adduct formed was determined using (32P)-postlabeling methods. Methoxyresorufin-O-demethylase (MROD) and ethoxyresorufin-O-deethylase (EROD) enzyme activities, which reflect CYP 1A activity, were measured as markers for phase I enzymes, and UDP-glucuronyltransferase (UGT) and glutathione S-transferase (GST) activities were determined as markers for phase II enzymes. Mice fed with a diet containing 0.5% purpurin for 3 days prior to MeIQx administration had 70% fewer MeIQx-DNA adducts in the lung and kidney, and fewer DNA adducts (insignificant, statistically) in the liver compared with mice fed a diet lacking purpurin. MROD and EROD activities in the liver of these mice increased six- and eight-fold, respectively, and were higher than those determined for the control mice within 1 day following commencement of purpurin treatment. These elevated activities were maintained during treatment and declined immediately following removal of purpurin from the diet. GST and UGT activities gradually increased 2.5- and 3-fold, respectively, following purpurin treatment, and were maintained at significantly high levels even after purpurin administration ceased. Alizarin did not significantly affect DNA-adduct formation and enzyme activity, except in the case of UGT. Taken together, /the/ results show that purpurin reduced MeIQx-DNA-adduct formation by maintaining elevated phase II enzyme activities, thereby facilitating accelerated excretion of MeIQx.

A single oral treatment of rats with MeIQx followed by phenobarbital, combined with further modulating procedures, stimulated development of foci of altered hepatocytes. Sequential administration of MeIQx after N-nitrosodiethylamine enhanced the appearance of foci of altered hepatocytes in rats.

The modifying effects of cigarette smoke (CS) exposure on a heterocyclic amine (HCA) 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx)-induced carcinogenesis were investigated in male F344 rats. Groups 1 and 2 were fed MeIQx at a dose of 300 ppm, and simultaneously received CS and sham smoke (SS) for 16 wk, respectively. Groups 3 - 5 were given the MeIQx diet for 4 wk, and simultaneously exposed to CS for 4 wk (group 3), exposed to CS for 12 wk after the MeIQx treatment (group 4), or received SS for 16 wk (group 5). Groups 6 and 7 were fed basal diet and respectively received CS and SS for 16 wk. In terms of the mean number or area, the development of glutathione S-transferase placental form-positive (GST-P(+)) liver cell foci was significantly (P < 0.01) greater in group 1 than in group 2. The mean number of colonic aberrant crypt foci (ACFs) per animal was increased by continuous CS exposure regardless of MeIQx feeding, the differences between groups 4 and 5 (P < 0.05), and between groups 6 and 7 (P < 0.05) being significant. Immunoblot analysis confirmed that the hepatic CYP1A2 level in group 6 was remarkably increased as compared to that in group 7. In addition, liver S9 from rats in group 6 consistently increased the mutagenic activities of six HCAs including MeIQx as compared to those in group 7. Thus, our results clearly indicate that CS enhances hepatocarcinogenesis when given in the initiation phase via increasing intensity of metabolic activation for MeIQx and possibly colon carcinogenesis when given in the post-initiation phase in rats induced by MeIQx.

... The effects of low doses of 2-amino-3,8-dimethyl-imidazo[4,5-f]quinoxaline (MeIQx) /were examined/ in combination with carbon tetrachloride (CCl4) on the formation of glutathione S-transferase placental form (GST-P)-positive foci in rat liver. Administration of diet containing MeIQx at 0.4, 4, or 40 ppm, representing one-thousandth, one-hundredth, and one-tenth of the dose proved to induce hepatocellular carcinomas (400 ppm), for 8 or 12 wk did not induce GST-P-positive foci. However, 40 ppm of MeIQx when co-administered with CCl4 (0.7 mL/kg, sc twice a wk) induced preneoplastic lesions: 7- and 3-fold increases in the numbers and areas of GST-P positive foci in wk 8, and 8- and 6-fold increases respectively in wk 12, over those with CCl4 alone. Furthermore, a marked increase in the number of hyperplastic nodules was observed in this group of rats in wk 12. No significant increases of GST-P-positive foci were observed at doses of 0.4 or 4 ppm MeIQx in combination with CCl4. Thus, it is predicted that chronic exposure to 40 ppm of MeIQx eventually results in induction of hepatocellular carcinomas in injured rat liver.

For more Interactions (Complete) data for 2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline (19 total), please visit the HSDB record page.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 2,500(SRC), determined from a structure estimation method(2), indicates that 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline is expected to have slight mobility in soil(SRC). The pKa of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline is estimated as 5.2(3), indicating that this compound will exist partially in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Volatilization of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 1.6X10-13 atm-cu m/mole(SRC), calculated using a fragment constant estimation method(5). 2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.7X10-8 mm Hg at 25 °C(SRC), determined from a fragment constant method(6). Biodegradation in soil data were not available(SRC, 2009).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 2,500(SRC), determined from a structure estimation method(2), indicates that 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 1.6X10-13 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 2(SRC), from a log Kow of 1.01(6) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is low(SRC). 2-Amino-3,8-dimethylimidazo[4,5-f]quinoline is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental condition(3). Biodegradation in water data were not available(SRC, 2009).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline, which has an estimated vapor pressure of 1.7X10-8 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 11 hours(SRC), calculated from its rate constant of 3.4X10-11 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). Particulate-phase 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline may be removed from the air by wet or dry deposition(SRC). 2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline contains chromophores that absorb at wavelengths >290 nm(4) and therefore may be susceptible to direct photolysis by sunlight(SRC).

2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline was detected in meat and chicken purchased from local Okayama, Japan markets, following cooking and analysis on the same day: in chicken, pork, well done beef and medium beef at 77, 202, 198 and 138 pg/g of sample, respectively(1). Food purchased at a supermarket in Little Rock, AK and cooked, contained 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline in pan fried beef at 1450, 3720 and 5310 pg/g of meat, in pan fried beef scrapings at 62,600 pg/g of meat, in barbequed beef at 527 and 1600 pg/g of meat, beef extract at 37,800 pg/g of meat and in barbequed chicken at 335 pg/g of meat(2).

PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/

Using a structure estimation method based on molecular connectivity indices(1), the Koc of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline can be estimated to be 2,500(SRC). According to a classification scheme(2), this estimated Koc value suggests that 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline is expected to have slight mobility in soil. The pKa of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline is estimated as 5.2(3), indicating that this compound will exist partially in the cation form in the environment and cations generally do adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4).

/EPIDEMIOLOGY STUDIES/ Although evidence suggests that consumption of well-done or grilled meat may be associated with increased cancer risk in humans, the data are insufficient to support the conclusion that this risk is due specifically to MeIQx present in these foods ... The presence of an individual heterocyclic amine (HCA) in cooked meat is highly correlated with the presence of other HCAs and with many other constituents, including protein, animal fat, nitrosamines, and substances other than HCAs formed during cooking, such as polycyclic aromatic hydrocarbons. It is therefore difficult to establish associations between cancer risk and specific HCAs.[DHHS/National Toxicology Program; Eleventh Report on Carcinogens: 2-Amino-3,8-Dimethylimidazo

/EPIDEMIOLOGY STUDIES/ ... During high temperature cooking of red meats, heterocyclic amines (HCAs) are generated; however, to be carcinogenic, they must be metabolized by enzymes including cytochrome P450 1A2 (CYP1A2) and N-acetyltransferase 1 (NAT1) and/or N-acetyltransferase 2 (NAT2) ... A clinic-based case-control study of colorectal adenomas ... focused on assessment of exposure to HCAs (estimated by use of a HCA database and meat cooking module) and modification of these exposures by genetic factors. /The authors/previously reported that intake of MeIQx was associated with an increased risk of colorectal adenomas [overall association at 80th percentile, > 27.00 ng/day: odds ratio (OR) = 2.68, 95% confidence interval (CI) 1.58-4.55]. Here, .... the evaluation of whether variation in CYP1A2, NAT1 and/or NAT2 modify the association between HCAs and colorectal adenoma formation in 146 cases and 228 frequency-matched controls /is reported/. The NAT1*10 allele was associated with a nonsignificant increased risk of colorectal adenomas (OR = 1.43; 95% CI 0.86-2.36). Further, when ... 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) intake /was analyzed/ as a categorical variable, ... a six-fold increase in adenoma risk among rapid NAT1 acetylators who consumed more than 27 ng/day (OR = 6.50; 95% CI 2.16-19.7) /was observed/, whereas among slow NAT1 acetylators, the increase in risk was two-fold (OR = 2.32; 95% CI 1.12-4.81). While suggestive, the results were not significantly different from each other on either an additive or multiplicative scale ...

/GENOTOXICITY/ In order to study the mutagenic effects of heterocyclic aromatic amines (HAAs) in cells of human origin, five compounds, namely 2-amino-3-methyl-imidazo[4,5-f]quinoline (IQ), 2-amino-3, 4-dimethyl-imidazo[4,5-f]quinoline (MeIQ), 2-amino-3, 8-dimethyl-imidazo[4,5-f]quinoxaline (MeIQx), the pyridoimidazo derivative 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), and 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1), were tested in micronucleus (MN) assays with a human derived hepatoma (HepG2) cell line. All HAAs caused significant, dose-dependent effects. The activities of IQ, MeIQ, MeIQx, and PhIP were similar (lowest effective concentrations 25-50 uM), whereas Trp-P-1 was effective at a dose of >/= 2.1 uM.

/GENOTOXICITY/ A co-expression plasmid (p1A2OR) carrying human CYP1A2 and NADPH-P450 reductase cDNAs and an expression plasmid (pOAT) carrying Salmonella TA1538/ARO cells. The CYP and OAT expressed in the Salmonella cells showed catalytic activity. The TA1538/ARO strain exhibited high sensitivity to heterocyclic amines (HCAs) such as 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ), 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,8-dimenthylimidazo[4,5-f]quinoline (MeIQx), 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) as compared with the parent Ames tester strain TA1538. It is suggested that the intracellular expression of drug-metabolizing enzymes makes the Salmonella cells highly sensitive to the HCAs.

For more Human Toxicity Excerpts (Complete) data for 2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline (7 total), please visit the HSDB record page.

2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline was detected in fish purchased from local Okayama, Japan markets, following cooking and analysis on the same day: in the skin and flesh of pacific saury 424 and 191 pg/g; in the skin and flesh of sardine at 860 and 152 pg/g; at 385 and 25 pg/g in the skin and flesh of horse mackerel; in the skin and flesh of mackerel at 588 pg/g and not detected; in the skin and flesh of salmon at 593 and 99 pg/g; not detected in the skin and flesh of salted atka mackerel; not detected in seasoned eel skin and flesh; in semi-dried horse mackerel skin and flesh at 420 pg/g(1).

2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline is formed and released in cooking fish(1), beef and chicken(1,2), resulting in its direct release to the environment. Its limited production and use for research purposes(3) may result in its release to the environment through various waste streams(SRC).[(1) Kataoka H et al; Bull Environ Contam Toxicol 69: 682-89 (2002) (2) Turesky RJ et al; J Agric Food Chem 53: 3248-58 (2005) (3) DHHS/National Toxicology Program; Eleventh Report on Carcinogens: 2-Amino-3,8-Dimethylimidazo

MeIQx (2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline)

Group 2B: Possibly carcinogenic to humans

Volume Sup 7: Overall Evaluations of Carcinogenicity: An Updating of IARC Monographs Volumes 1 to 42, 1987; 440 pages; ISBN 92-832-1411-0 (out of print)

1993

1992

An estimated BCF of 2 was calculated in fish for 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline(SRC), using a log Kow of 1.01(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

The Henry's Law constant for 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline is estimated as 1.6X10-13 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline is expected to be essentially nonvolatile from water surfaces(2). 2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.7X10-8 mm Hg(SRC), determined from a fragment constant method(3).

2-Amino-3,8-dimethylimidazo(4,5-f)quinoxaline (MeIQx) ... and its isotopically labelled ([13]C, [15]N2 and [14]C) analogues were synthesized and used for metabolic studies in vivo. An equimolar mixture of MeIQx and its [13]C, [15]N2 stable isotope labelled analogue (containing tracer amounts of [14]C-MeIQx) was given ip to mice. Some 67% of the radioactivity was eliminated in urine and feces within 24 hr. Four radiolabelled species were observed when urine was analysed by HPLC, corresponding to unchanged MeIQx and three more polar metabolites. Urine was analysed directly by HPLC-thermospray mass spectrometry. Four signals were observed containing the characteristic 1:1 isotopic doublet, corresponding to unchanged MeIQx, an MeIQx glucuronide, and two uncharacterized metabolites.

Adduct formation has been considered to be a major causal factor of DNA damage by carcinogenic heterocyclic amines. By means of experiments with (32)P-labeled DNA fragments and an electrochemical detector coupled to a high-pressure liquid chromatograph, we investigated whether the N-hydroxy metabolite of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) can cause oxidative DNA damage or not. This metabolite [MeIQx(NHOH)] was found to cause Cu(II)-mediated DNA damage, including 8-oxo-7,8-dihydro-2'-deoxyguanosine formation. When an endogenous reductant, beta-nicotinamide adenine dinucleotide (NADH), was added, the DNA damage was greatly enhanced. Catalase and bathocuproine, a Cu(I)-specific chelator, inhibited the DNA damage, suggesting the involvement of H2O2 and Cu(I). MeIQx(NHOH) frequently induced DNA cleavage at thymine and cytosine residues in the presence of NADH and Cu(II). A UV-visible spectroscopic study showed that little decomposition of MeIQx(NHOH) occurred in the absence of Cu(II), whilst rapid spectral change was observed in the presence of Cu(II), suggesting that Cu(II) catalyzes the autoxidation. The addition of NADH reduced the oxidized product back to MeIQx(NHOH). These results suggest that a copper-peroxo intermediate, derived from the reaction of Cu(I) with H2O2, participates in Cu(II)-dependent DNA damage by MeIQx(NHOH), and NADH enhances the DNA damage via a redox cycle. /It was concluded/ that in addition to DNA adduct formation, oxidative DNA damage plays an important role in the carcinogenic process of MeIQx. /MeIQx (NHOH)/

2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), one of the most abundant of the heterocyclic aromatic amines formed during the cooking of meat, is genotoxic and carcinogenic in rodents. MeIQx requires metabolic activation by P450 before it can exert these effects. While there is indirect evidence that the mutagenic product is N-hydroxy-MeIQx (N-OHMeIQx), ... this /was identified/ unequivocally following incubation of the amine with human hepatic microsomal fraction. A mixture of unlabelled MeIQx, (13C,15N2)MeIQx and (14C)MeIQx was used as substrate and the products analysed by HPLC-thermospray mass spectrometry. Characteristic doublet ions, 3 mass units apart, were found at m/z 214/217 ([M+H]+) from the parent compound, MeIQx and at 230/233 ([M+H]+) from N-OHMeIQx. The presence of a doublet ion at m/z 214/217 with the doublet at 230/233 [M+H+] provided additional evidence that this was N-OHMeIQx, as facile loss of 'O' is characteristic of N-hydroxylamines. Further evidence for the identity of the major metabolite, which accounted for approximately 90% of all microsomal metabolism, was obtained by comparing the mutagenicity of the HPLC eluate using Salmonella typhimurium YG1024, which is particularly sensitive to N-hydroxylamines, and TA98/1,8-DNP6 which is resistant to most N-hydroxylamines. Ninety-five per cent of direct-acting mutagenicity present in the reaction mixture was associated with a single peak, which co-eluted with N-OHMeIQx, as indicated by mass spectrometry. In the presence of a metabolic activation system, only one additional mutagenic peak, corresponding to unchanged MeIQx, could be detected. MeIQx (5 microM) was N-hydroxylated at a rate of 77 +/- 11 pmol/mg/min (mean +/- SEM, n = 4) by human liver microsomes. The specific inhibitor of human CYP1A2, furafylline (5 uM) inhibited the N-hydroxylation of MeIQx by > 90%. These data show that N-OHMeIQx is both the major oxidation product and the major genotoxic product of MeIQx generated by microsomal fractions of human liver and that the reaction is catalysed almost exclusively by CYP1A2.

The disposition and metabolism of ... 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) was studied in rats. After a single oral dose of 20 mg (14)C-labeled MeIQx/kg bw, three major non-mutagenic metabolites were identified. These were 2-amino-4(or 5)-(beta-D-glucuronopyranosyloxy)-3,8-dimethylimidazo[4,5-f] quinoxaline, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxalin-4(or 5)-yl sulfate and N-(3,8-dimethylimidazo[4,5-f]quinoxalin-2-yl) sulfamate. Another two metabolites present in bile, urine and feces were 2-(beta-D-glucuronopyranosylamino)-3,8-dimethylimidazo[4,5-f ] quinoxaline and 2-amino-8-hydroxymethyl-3-methylimidazo[4,5-f]quinoxalin-4 (or 5)yl sulfate. All metabolites were essentially non-mutagenic. Most of the mutagenicity still present in bile, urine and feces could be explained by unchanged MeIQx. Unchanged MeIQx was the most abundant form excreted in urine.

For more Metabolism/Metabolites (Complete) data for 2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline (20 total), please visit the HSDB record page.

Meiqx has known human metabolites that include IQx-8-COOH and N-HydroxyMeIQX.

Substances that increase the risk of NEOPLASMS in humans or animals. Both genotoxic chemicals, which affect DNA directly, and nongenotoxic chemicals, which induce neoplasms by other mechanism, are included.

Chemical agents that increase the rate of genetic mutation by interfering with the function of nucleic acids. A clastogen is a specific mutagen that causes breaks in chromosomes.

Cooking meat, fish, or poultry at high temperature gives rise to heterocyclic aromatic amines (HAAs), which may be metabolically activated to mutagenic or carcinogenic intermediates. The enzymes cytochrome P4501A2 (CYP1A2) and N-acetyltransferase (NAT2) are principally implicated in such biotransformations ... The relationship between the activity of these two enzymes and the urinary excretion of unmetabolized and Phase II conjugates of the two HAAs MeIQx (2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline) and PhIP (2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine) /was determined/ in individuals fed a uniform diet containing high-temperature cooked meat. The subjects in the study ate meat containing known amounts of MeIQx and PhIP, and urine collections were made 0-12 and 12-24 hr after a meal. MeIQx and PhIP were measured in urine after acid treatment that quantitatively hydrolyzes the Phase II conjugates to the respective parent amine. The extracts containing the HAAs were purified by immunoaffinity chromatography and analyzed by liquid chromatography using electrospray ionization-tandem mass spectrometry. The MeIQx content in the 0-12 hr urine increased after acid hydrolysis by a factor of 3-21-fold. After acid treatment, the total amount of MeIQx (unmetabolized plus the N2-glucuronide and sulfamate metabolites) excreted in the 0-12 hr urine was 10.5 +/- 3.5% (mean +/- SD) of the dose, whereas the total amount of PhIP (unmetabolized plus acid-labile conjugate(s)) in the 0-12 hr period was 4.3 +/- 1.7% (mean +/- SD) of the dose. The total amount of PhIP in the 12-24 hr urine after acid treatment was 0.9 +/- 0.4% (mean +/- SD) of the dose. Linear regression analysis of the amounts of MeIQx and PhIP excreted in the 0-12 hr period expressed as a percentage of the ingested dose, for all subjects, gave a low but significant correlation (r = 0.37, P = 0.005). Linear regression analyses showed that lower total MeIQx (unmetabolized plus the N2-glucuronide and sulfamate metabolites) in urine was associated with higher CYP1A2 activity, whereas total PhIP (unmetabolized plus conjugated) in urine showed no association to CYP1A2 activity. These results indicate that in humans, MeIQx metabolism and disposition are more strongly influenced by CYP1A2 activity than are those of PhIP. Linear regression analysis found no association between NAT2 activity and the levels (unmetabolized plus acid-labile conjugates) of MeIQx or PhIP excreted in urine.

The kinetics of distribution of radiolabelled [2-14]C-IQ (2-amino-3-methylimidazo[4,5-f]quinoline) and [2-14]C-MeIQx (2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline) following the oral administration to BALB/c mice of single doses were studied. Both compounds were taken up into the blood-stream and other tissues rapidly after administration, and approx 20-25% of the radioactive dose of IQ or MeIQx was excreted in urine over 6 hr, reflecting the rapid absorption of the mutagens. Significantly greater levels of MeIQx than IQ were isolated from the lungs and blood of treated mice. In studies of the uptake of IQ from closed sections of the gut, little IQ was absorbed from the stomach. Although there was some evidence that it could be absorbed from the large intestine, the primary site of IQ absorption was the small intestine.

The absorption and kinetics of excretion of (14)C-2-amino-3,8-dimethylimidazo[4,5-f]-quinoxaline (MeIQx) was studied in male Sprague-Dawley rats. Within 72 hr of an oral dose of (14)C-MeIQx (20 mg/kg) 33-56% of the radioactivity was excreted in the urine and 37-75% of the radioactivity in the feces, which accounted for greater than 99% of the dose. Only low levels of radioactivity remained in the body. Radioactivity, when expressed per gram of tissue, was highest in the liver and kidney with smaller amounts detected in the lung and both the small and large intestines. Between 25 and 50% of a dose of MeIQx was recovered in the bile within 24 hr. Biliary metabolites were excreted over a long period of time with one radioactive fraction rapidly excreted at 2-3 hr and a second fraction excreted at 10-12 hr. The metabolites present in bile were assessed for genotoxicity using Salmonella typhimurium TA98 with or without hepatic S-9 activation and were found to be present as detoxified products. The residual mutagenic activity present in bile was attributed primarily to unmetabolized MeIQx.

The disposition and metabolism of ... 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) was studied in rats. Five rats of both sexes were given a single oral dose of (14)C-labeled MeIQx (3-4 mg/kg bw). The male rats excreted 36% of the radioactivity and 15% of the mutagenic activity of the dose given in the urine collected during the first 24 hr. In the females the corresponding urine contained 41% of the radioactivity and 12% of the mutagenicity. During the next 48 hr only 1-3% of the radioactive dose was excreted in urine. The remaining dose was excreted in the feces except for less than 1% that was retained by the tissues after 72 hr. The liver and kidney retained more radioactivity than other organs.

For more Absorption, Distribution and Excretion (Complete) data for 2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline (10 total), please visit the HSDB record page.

Strong mutagen found in broiled foods. [ChemIDplus] Naturally produced when meats are heated or cooked; Used as a research chemical; [HSDB]

No known commercial use.[DHHS/National Toxicology Program; Eleventh Report on Carcinogens: 2-Amino-3,8-Diemethylimidazo

MeIQx was prepared in 21% overall yield from 4-fluoro-o-phenylenediamine. The 3,7-dimethyl isomer may be obtained as a minor by-product. The [14]C-label was introduced in the last step through cyclization with [14]C-cyanogen bromide. An alternative synthesis of MeIQx from p-fluoroaniline avoided the separation of isomers but gave poorer yield.

MeIQx is produced in small quantities for research purposes. It is formed naturally during the cooking of muscle-derived foods (meat and fish) as by-products of the Maillard (or browning) reaction. It is postulated that the amino-imidazo part of /heterocyclic amines/ (HCAs) is formed from creatine, while the remaining parts of the compound are likely formed from Strecker degradation products, such as pyridines or pyrazines, which are formed in the Maillard reaction between hexose sugars and amino acids. Formation of HCAs in food reportedly is affected by temperature, processing time, acidity, precursor concentrations, and types of amino acid present. In general, higher temperatures and longer cooking times increase the amount of HCAs produced. HCA formation also increases with cooking methods that use direct or efficient transfer of heat from the source to the food; frying or grilling of muscle meats produces more HCAs than do indirect-heat methods such as stewing, steaming, or poaching.[DHHS/National Toxicology Program; Eleventh Report on Carcinogens: 2-Amino-3,8-Dimethylimidazo

... heterocyclic amine formed during heating or cooking and /is/ found in cooked meat and fish