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.
来源:Hazardous Substances Data Bank (HSDB)
代谢
美克酸是人类代谢物,包括IQx-8-COOH和N-羟基美克酸。
Meiqx has known human metabolites that include IQx-8-COOH and N-HydroxyMeIQX.
There is inadequate evidence in humans for the carcinogenicity of MeIQx. There is suffcient evidence in experimental animais for the carcinogenicity of MeIQx. Overall evaluation: MeIQx (2-Amino-3,8-dimethylimidazo(4,5-j)quinoxaline) is possibly carcinogenic to humans (Group 2B).
MeIQx is reasonably anticipated to be a human carcinogen based on sufficient evidence of carcinogenicity in experimental animals and supporting genotoxicity data.[DHHS/National Toxicology Program; Eleventh Report on Carcinogens: 2-Amino-3,8-Dimethylimidazo
来源:Hazardous Substances Data Bank (HSDB)
毒理性
致癌物分类
国际癌症研究机构致癌剂:MeIQx
IARC Carcinogenic Agent:MeIQx
来源:International Agency for Research on Cancer (IARC)
毒理性
致癌物分类
国际癌症研究机构(IARC)致癌物分类:2B组:可能对人类致癌
IARC Carcinogenic Classes:Group 2B: Possibly carcinogenic to humans
来源:International Agency for Research on Cancer (IARC)
IARC Monographs: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)
来源:International Agency for Research on Cancer (IARC)
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.
A potent mutagen, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (Me-IQx), isolated from fried beef and its 3,7-dimethyl derivative were synthesized from 6-amino-3-methylquinoxa1ine and 6-amino-2-methylquinoxaline, respectively. These compounds showed strong mutagenic activity towards Salmonella typhimurium TA98 in the presence of S9 Mix.
Regioselective Differences in C<sup>8</sup>- and N-Oxidation of 2-Amino-3,8-dimethylimidazo[4,5-<i>f</i>]quinoxaline by Human and Rat Liver Microsomes and Cytochromes P450 1A2
作者:Robert J. Turesky、Véronique Parisod、Tuong Huynh-Ba、Sophie Langouët、F. Peter Guengerich
DOI:10.1021/tx010035s
日期:2001.7.1
The metabolism of the mutagen 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) was investigated with human and rat liver microsomes, recombinant humancytochromeP4501A2 (P4501A2) expressed in Escherichia coli cells, and rat P4501A2. Human liver microsomes and humanP4501A2catalyzed the oxidation of the exocyclic amine group of MeIQx to form the genotoxic product 2-(hydroxyamino)-3,8-dimethylimidazo[4
Metabolism of 2-Amino-3,8-dimethylimidazo[4,5-<i>f</i>]- quinoxaline in Human Hepatocytes: 2-Amino-3-methylimidazo[4,5-<i>f</i>]quinoxaline-8-carboxylic Acid Is a Major Detoxication Pathway Catalyzed by Cytochrome P450 1A2
作者:Sophie Langouët、Dieter H. Welti、Nathalie Kerriguy、Laurent B. Fay、Tuong Huynh-Ba、Jovanka Markovic、F. Peter Guengerich、André Guillouzo、Robert J. Turesky
DOI:10.1021/tx000176e
日期:2001.2.1
8-dimethylimidazo[4,5-f]quinoxaline, which is formed by cytochromeP4501A2 (P4501A2), was found to be transformed into the N(2)-glucuronide conjugate, N(2)-(beta-1-glucosiduronyl)-2-(hydroxyamino)-3,8-dimethylimidazo[4,5-f]quinoxaline. The phase II conjugates N(2)-(3,8-dimethylimidazo[4,5-f]quinoxalin-2-yl)sulfamic acid and N(2)-(beta-1-glucosiduronyl)-2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline, as well
Metabolism of the Food-Borne Mutagen 2-Amino-3,8-dimethylimidazo[4,5-<i>f</i>]quinoxaline in Humans
作者:Robert J. Turesky、R. Colin Garner、Dieter H. Welti、Janique Richoz、Steve H. Leveson、Karen H. Dingley、Kenneth W. Turteltaub、Laurent B. Fay
DOI:10.1021/tx9701891
日期:1998.3.1
8-dimethylimidazo[4,5-f]quinoxalin-2-yl)sulfamic acid (MeIQx-N2-SO3(-)) and N2-(beta-1-glucosiduronyl)-2-amino-3,8-dimethylimidazo[4,5-f ]quinoxaline (MeIQx-N2-Gl). Two other metabolites were the cytochrome P450-mediated (P450) oxidation products 2-amino-8-(hydroxymethyl)-3-methylimidazo[4,5-f]quinoxaline (8-CH2OH-MeIQx), and N2-(beta-1-glucosiduronyl)-N-hydroxy-2-amino-3,8-dimethylimidaz o[4,5-f]quinoxaline (NOH-MeIQx-N2-Gl)
Silica gel linked to a phthalocyanine compound and a method for treating polycyclic organic substances therewith
申请人:SUMITOMO CHEMICAL COMPANY, LIMITED
公开号:EP0157549A2
公开(公告)日:1985-10-09
Silica gel is treated with a reactive phthalocyanine compound to form the blue silica gel, which has a phthalocyanine keleton linked through an organic group. Typically, a phthalo- yanine reactive dye is used for the reaction with silica gel at :s hydroxyl or other reactive site. The blue silica gel easily ad- orbs and desorbs the polycyclic organic substances in a solu- ion. The blue silica gel can be used for the separation or re- noval of the mutagenic substances from the environment, oodstuffs, etc.