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1.
By monitoring the mutagenicity to a new Salmonella tester strain,YG1024, which has a much higher level of 0- acetyltransferaseactivity than S.typhimurium TA98, we found two new mutageniccompounds in bacteriological-grade beef extract. One of them(compound I), which had a similar UV spectrum to that of 2-amlno-3,4,8-trimethylimidazo[4,5-f]quinoxaline (4,8-DiMeIQx), was isolated and shown toaccount for {small tilde}2% of the total mutagenicity of thematerials adsorbed to blue cotton, and its concentration wasestimated to be 6.0 ng/g beef extract. This amount of compoundin beef extract was insufficient to allow measurements of variousspectra, but its level was increased {small tilde}9-fold byheating beef extract with creatine and threonine at 200°Cfor 5 h. From UV and mass spectra of the compound obtained frombeef extract heated with creatine plus threonine, it was deducedto be a hydroxymethyl derivative of anminodimethylimidazoquinoxaline.Compound I was isolated from the urine of rats given 4,8-DiMeIQxand identified as 2-amino-4-hydroxymethyl-3,8-dimethylimidazo[4,5-f]quinoxaline (4-CH2OH-8-MeIQx) by 1H-NMR analysis. 4-CH2OH-8-MeIQxinduced 326 000 revertants of YG1024 and 99 000 revertants ofTA98 per µg in the presence of S9 mix.  相似文献   

2.
Monoclonal mouse IgG1 and IgG3 antibodies were developed tothe food mutagens, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine(PhIP) and 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline(4,8-DiMeIQx) in order to make specific and sensitive detectionand purification systems suitable for biological samples. Theantibodies were developed with the strategy that cross-reactionwith analogues modified in the N2-position was desirable. Competitiveenzyme-linked immunosorbent assays (ELISA) with 50% inhibitionby 0.4–6 pmol food mutagen were developed. The epitopesrecognized by the antibodies have been characterized by ELISAusing 52 synthetic analogues and metabolites of PhIP, 4,8-DiMeIQx,and other food mutagens. One of the anti-PhIP antibodies onlyrecognizes PhIP and those PhIP-analogues which have minor modificationsin the N2-amino group, whereas the other, 7B7-1, is less stringentand also recognizes several other modified metabolites, includingbulky adducts at the N2-amino group e.g. the major guanine anddeoxyguanosine adducts isolated from PhIP-modified DNA. Theantibodies to DiMeIQx also recognize the food mutagens 2-amino-3,4-dimethylimidazo[4,5-f]quinoxaline(4-MeIQx), 2-amino-3, 8-dimethylimidazo[4, 5-f]quinoxaline (8-MeIQx),and the corresponding quinolines (4-MeIQ and 8-MeIQ). Two ofthese antibodies only bind analogues with minor modificationsin the free amino group, whereas analogues with major modificationsin this position, including a deoxyguanosine adduct, react withthe third antibody. Urine samples and faecal extracts from 3H-PhIPor 2-14C-DiMeIQx dosed rats were analysed by these ELISA assays,and high correlations between radioactivity and response inthe ELISA assays were observed. Urine samples and faecal extractsfrom 3H-PhIP-dosed rats were purified on an affinity columncontaining the less stringent anti-PhIP antibody, 7B7-1. Theaffinity column was found by high performance liquid chromatography(HPLC) analysis to concentrate exclusively labelled material.This affinity column also bound PhIP-related materials fromdilute samples of acid hydrolysed PhIP-DNA with high efficiency.Only  相似文献   

3.
Food-derived aminoimidazoazarenes have been shown to be mutagenicand carcinogenic and to form covalent DNA adducts. 32P-Post-labellinganalysis of DNA modified with these heterocyclic amines (HA),including 2-amino-3-methyl-imidazo[4,5-f]quinoline (IQ), 2-amino-1-methyl-6-phenylimid-azo[4,5-b]pyridine(PhIP), 2-amino-3,4-dimethylimidazo [4,5-fquinoline (MeIQ),2-amino-3,4,8-trimethylimidazo [4,5-f1 quinoxaline (4,8-DiMeIQx),2-amino-3,7,8-trimethylimidazo[4,5-f]quinoxaline (7,8-DiMeIQx)and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) hasresulted in considerable interlaboratory variation in the characteristicpatterns of DNA adduct spots, with up to six being detectedfor each compound. Similar complex patterns were observed whenazido-derivatives of HA were photoreacted with calf thymus DNA.When deoxyguanosine 3'-monophosphate was modified with the azidoderivatives and analysed using the 32P-post-labelling procedure,one major spot was observed for IQ, 4,8-DilMeIQx, 7,8-DiMeIQxor PhIP and two major spots for MeIQ or MeIQx. In each case,these adducts were chromatographically indistinguishable fromthe major adducts formed with DNA. No major adduct spots wereobserved when 3'-phosphate derivatives of deoxyadenosine, deoxycytidineor thymidine were reacted with the azido-derivatives of HA.In an attempt to identify the additional spots, azido derivativesof PhIP or IQ were reacted with the synthetic homopolymer poly(dG)·poly(dC),the alternating copolymer poly(dC-dG) or a synthetic oligonucleotide(TTT-GTTTTTTCTTTCCCT): in each case a reduced number of adductspots were detected. The introduction of an additional nucleaseP1 hydrolysis step following the labelling reaction furtherreduced the number of adduct spots to only one or two majorspots. Reversed-phase HPLC analysis showed that the number ofpeaks of radioactivity was also reduced to one or two, presumablycorresponding to the [32P]-5'-monophosphate deoxyguanosine adducts.We suggest that many of the additional spots commonly observedin conventional 32P-post-labelling analysis of HA-modified DNAare adducted oligonucleotides that are partly resistant to hydrolysisby micrococcal nuclease and spleen phosphodiesterase but aresusceptible to hydrolysis by nuclease P1.  相似文献   

4.
Mixtures of creatinine, glucose and threonine with the additionof a small amount, 250 µCi, of [U-14C]glucose, [1-14C]glucoseor [6-14C]glucose were heated at 180°C for 30 min in anaqueous model system. The mixtures were purified and analysedusing HPLC, scintillation and Ames tests. 2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline(MeIQx) and 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline(4,8-DiMeIQx) were detected as the main radioactive mutagens.The amount of MeIQx and 4,8-DiMeIQx produced from threoninewas estimated at 18 and 60 nmol/mmol glucose respectively. Radioactivecarbon atoms originating from glucose were also shown to beincorporated into 2-amino-3-methylimidazo[4,5-f]quinoxaline(IQx). The specific activity was calculated to be 0.6, 0.3 and0.1–0.3 mCi/mmol for MeIQx, 4,8-DiMeIQx and IQx respectivelyfor all three labelled forms of glucose. By the incorporationof carbon atoms originating from glucose into the imidazoquinoxalinemutagens it was clearly demonstrated that glucose is a precursorin the formation of these food mutagens.  相似文献   

5.
The metabolic fate of 2-amino-3,8-dimethylimidazo[4,5-f] quinoxaline(MeIQx), a carcinogen formed in cooked meat and fish, has beeninvestigated in male Sprague-Dawley rats. Five metabolites wererecovered from bile of animals given an intragastric dose of{2-14C]MeIQx. These accounted for nearly all of the radioactivityin bile. The chemical structures of these metabolites were elucidatedby proton NMR, UV and mass spectroscopy. Three structures maybe assigned unambiguously: two sulfamates, N-(3,8.dimethylimidazo[4,5f]quinoxalin-2-yl)sulfamic acid and N-(8-hydroxymethyl-3-methylimidazo[4,5f]quinoxalin-2-yl)sulfamic acid, and N-(8-one glucuronide, N2(ß-1-glucosiduronyl)-2-amino-3,8-dimelhyliinidazo[4,5f]quinoxaline In addition, an acetyl and a glucosiduronylconjugate of 5-hydroxy-MeIQx were observed. The spectral evidencedid not allow an unambiguous assignment of the site of conjugation.The two glucuronides were excreted in urine and the sulfamateof MeIQx was found in feces as well as urine. All five metaboliteswere found to be non-mutagenic to Salmonella typhimurium TA98with or without metabolic activation. The glucuronide conjugateswere found also to be non-mutagenic when ß- glucuronidasewas incorporated with S-9 mixture in the mutation assay, andthus all appear to be detoxification products. The previouslyreported metabolite, 2-amino-8-hydroxymethyl-3-methylimidazo[4,5f]quinoxalinewhich is mutagenic to Salmonella typhimurium TA98 with metabolicactivation, was identified as a minor component in both urineand feces.  相似文献   

6.
2-Amino-3, 8-dimethylimidazo[4, 5-f]quinoxaline (MelQx) wastransformed to at least 10 metabolites in suspensions of hepatocytesisolated from Aroclor 1254 treated rats. Combining biochemicaldata such as effects on MeIQx metabolism of metabolic modulatorsand incorporation of radioisotopic sulfur with UV, mass and1H-NMR spectroscopy, we elucidated the structures of six metabolites.About 40% of the MeIQx was transformed to 2-amino-3, 8-dimethylimidazo[4,5-f]quinoxalin-4(or5)-yl sulfate. Other oxygenated metaboliteswere 2-amino-8-hydroxymethy1–3-methylimidazo[4, 5-f)quinoxalin-4(or5)-yl sulfate and 2-amino-4(or5)-ß-D-glucuronopyranosyloxy-3,8-dimethylimidazo[4, 5-f]quinoxaline. Evidence was obtainedthat a glutathione conjugate was formed. This metabolite, andthe other oxygenated metabolites were probably formed in P-450catalyzed reactions. Two metabolites, 2-ß-D-glucurono-pyranosylamino-3,8-dimethylimidazo[4, 5-f)quinoxaline and the N(3, 8-dimethylimidazo[4,5-f]quinoxaline-2-yl)sulfamate, were direct conjugates of MeIQx.  相似文献   

7.
A gas chromatographic—mass spectrometric assay has beendeveloped for the simultaneous measurement of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline(MeIQx) and 2-amino-3,4,8-dimethylimidazo[4,5-f]quinoxaline(DiMeIQx) in fried beef. The method employs capillary columngas chromatography, electron capture negative ion chemical ionisationmass spectrometry and a stable isotope labelled analogue ofMeIQx (the synthesis of which is described) as common internalstandard. Two patties of lean minced beef which had been cookedseparately were analysed and found to contain both compounds(patty 1–2.4 ng MeIQx/g meat, 1.2 ng DiMeIQx/g meat; patty2–1.3 ng MeIQx/g meat, 0.5 ng DiMeIQx/g meat). Neithercompound was present in the meat prior to cooking.  相似文献   

8.
A metabolite of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline(MeIQx) was incorrectly characterized in this paper. The metabolitewas thought to be an acetyl conjugate of the 5-hydroxyl-atedderivative of MeIQx. This assignment is incorrect. The correctassignment is a sulfate conjugate of 5-hydroxy-MeIQx, 2-amino-3,8-dimethylirnidazo[4,5-f]quinoxaUn-5-yl-sulfate.This conclusion is based upon repurified sample analyzed by1H NMR and 13C NMR, enzyme hydrolysis assays, IR spectro-scopyand FAB/MS (accurate mass measurement).  相似文献   

9.
A simple and efficient method for the purification of mutagenicheterocyclic amines from heated meat products has been developed.In only two steps, namely extraction of raw material on Kieselgurfollowed by medium pressure liquid chromatography on SephasorbHP, very clean fractions with high recovery rates of mutageniccompounds were obtained, thus allowing isolation and quantitationby high performance liquid chromatography (HPLC) with UV detection.The method was validated on both food grade and bacterial beefextracts as well as fried beef. In 1–5 gsamples of beefextracts, levels up to 70 p.p.b. (ng/g) of 2-amino-3-methyl-imidazo[4,5-f]quinoline(IQ), 8–90 p.p.b. of 2-amino-3, 8-di-methylimidazo[4,5-f]quinoxaline (MeIQx) and up to 8 p.p.b. of 2-amino-3, 4,8-trimethylimidazo[4, 5-f]quinoxaline (4, 8-DiMeIQx) were determined.In fried beef, 1p.p.b. of 2-amino-1-methyl-6phenylimidazo[4,5-b]pyridine(PhIP) and 1 p.p.b. of MeIQx were measured. Thequantitative results of beef samples were in agreement withresults from determinations using immunoaffinity chromatography/HPLCor liquid chromatography coupled with mass spectrometry. MeIQxcould be quantified in fried beef down to 1ng/g of fresh beefmaterial. According to assays performed with reference standardsof tryptophan and glutamic acid pyrolysis products, the methodcould also be extented to quantitate other heterocyclic amines.  相似文献   

10.
A simple and sensitive method was developed for quantificationof mutagenic/carcinogenic aminoimidazoquinoline and aminoimidazoquinoxalinecompounds in heated materials. Samples were partially purifiedby blue-cotton treatment, 0.1 N HCI-methylene dichloride partitionand separation in a SEP-PAK silica cartridge. The recoveriesof aminoimidazoquinoline and aminoimidazoquinoxaline compoundsat the step of partial purification were estimated by spikingwith 14C-labeled compounds. The compounds in partially purifiedmaterials were analyzed by liquid chromatography with electrochemicaldetection using a combination of two columns of octadecyl silaneand cation exchange. Bacteriological-grade beef extract wasfound to contain 41.6 and 58.7 ng/g of 2-amino-3-methylimidazo[4,5-f]quinoline and 2-amino-3, 8-dimethylimidazo[4, 5-f]quinoxaline(MeIQx), respectively. MeIQx was also detected at a level of3.1 ng per g in food-grade beef extract.  相似文献   

11.
Frequent consumers of meat have an increased risk of colorectalcancer and possibly also of breast, stomach, pancreas and urinarybladder cancer. Bacon, ‘Falusausage’, ground beef,meatballs, pork belly, pork chops and sliced beef account formore than one-third of the intake of fried meat of the populationof Stockholm of age 50–75. These dishes were fried atfour temperatures (150, 175, 200 and 225 °C) representingnormal household cooking practices in Stockholm. Heterocyclicamines in these dishes were analysed using solid-phase extractionand HPLC. The heterocyclic amines 2-amino-3-methylimidazo[4,5-f]quinoline(IQ), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx),2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (DiMeIQx) and2-amino-1-methyl-6-phenylimidazo[4,5-b]-pyridine (PhIP) wererecovered. The formation of IQ was favoured by moderate cookingtemperatures; IQ was detected in one meat sample cooked at 150°Cand in some pan residues. The yield of MeIQx, DiMeIQx and PhIPincreased with the temperature. For several of the meat dishes,the content of heterocyclic amines in the pan residue was aslarge or larger than for corresponding piece of meat. The highestlevels of MeIQx were 23.7 ng/g in the meat and 233 ng/g in thepan residue. Corresponding data for DiMeIQx were 2.7 and 4.1ng/g and for PhIP 12.7 and 82.4 ng/g. The study leaves littledoubt that mutagenic heterocyclic amines are ingested by thepopulation of Stockholm, and added to previous epidemiologicalstudies from the same area, the combined data are consistentwith human carcinogenicity of heterocyclic amines. However,analytical epidemiological studies are needed before any statementon causality can be made.  相似文献   

12.
One of the mutagenic and carcinogenic heterocyclic amines (HCAs),2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MelQx), is presentin cooked foods and we are chronically exposed to this compoundin our daily life. To study the role of HCAs in human carcinogenesis,we analyzed MelQx-DNA adducts in 38 DNA samples obtained fromsurgical and autopsy specimens by the 32P-postlabeling methodunder adduct-intensification conditions with the modificationof additional digestion with nuclease P1 and phosphodiesteraseI after 32P-labeling at 5' -hydroxyl termini. This modified32P-postlabeling method can detect N2-(deoxyguanosin-8-yl)-2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline 5'-monophos-phate (5'-pdG-C8-MeIQx) at levelsdown to 1/1010 nucleo-tides. The DNA samples from colon andrectum surgical specimens and a kidney taken at autopsy werefound to contain an adduct spot corresponding to that of standard5'-pdG-C8-MeIQx on TLC at levels of 14, 18 and 1.8 per 1010nucleotides, respectively. Each adduct spot was extracted fromTLC and identified to be 5'-pdG-C8-MeIQx by HPLC. Thus, MelQx-DNAadducts actually exist in human tissues and this adduct formationmay be involved in human cancer development.  相似文献   

13.
Cultures of human mammary epithelial cells were treated withone of seven heterocyclic amine food mutagens [2-amino-3-methylimidazo[4,5-f)quinoline (IQ), 2-amino-3, 4-dimethylimidazo[4, 5-f)quinoline(MelQ), 2-amino-3, 8-di-methylimidazo[4, 5-f]quinoxaline (MeIQx),2-amino-3, 4, 8-trimethylimidazo[4, 5-f]quinoxaline (4, 8-DiMelQx)2-amino-3, 7, 8-trimethylimidazo[4, 5-f]quinoline (7, 8-DiMelQx),2-amino-3, 4, 7, 8-tetramethylimidazo[4, 5-f]quinoxaline (4,7, 8-TriMelQx) or 2-amino-1-methy1–6-phenylimidazo[4,5-b] pyridine (PhlP)], four nitropyrenes (1-nitropyrene (1-NP),1, 3-dinitropyrene (1, 3-DNP), 1, 6-dinitropyrene (1, 6-DNP)or 1, 8-dinitropyrene (1, 8-DNP) or the Polycyclic aromatichydrocarbon dibenzo[a, l]pyrene (DB[a, l]P). DNA isolated fromthe cultures was analysed by 32P-post-labelling and in eachcase the presence of carcinogen-DNA adducts was detected. Thepatterns and numbers of adducts obtained when human mammarycell DNA digests were separated on polyethyleneimine-celluloseTLC were found to closely resemble those previously demonstratedto be present in the DNA of tissues from rodents and other primatestreated with the same agents. Up to six DNA adducts were detectedin human breast cells treated with IQ and MelQ. Fewer adducts(1–3) were detected following treatment with MelQx orits methylated derivatives, whilst PhIP gave rise to at leastfour distinct adduct spots. Five adduct spots were detectedin breast cells treated with DB[a, l]P or with 1-NP, but feweradduct spots were formed by 1, 3-, 1, 6- and 1, 8-DNP. Thesedata demonstrate the ability of human breast epithelial cellsto activate to DNA binding species a range of carcinogenic compoundsknown to be present in the human diet or to which humans areknown to be exposed environmentally.  相似文献   

14.
The 32P-postlabeling method was used to examine the adductsin DNA, polynucleotides, and mononucleotides reacted in vitrowith the N-hydroxy and N-acetoxy derivatives of 2-amino-3-methylimidazo[4,5-f]quinoline(IQ), 2-amino-3, 8-dimethylimidazo[4,5-f]quinoxaline (MelQx)or 2-amino-1-methy1-6-phenylimidazo[4,5-b]pyridine (PhIP). Adductprofiles were compared to those found in vivo in liver of cynomolgusmonkeys fed IQ, MeIQx or PhIP. The N-acetoxy derivatives ofIQ, MelQx and PhIP (generated in situ from the correspondingN-hydroxylamine in the presence of acetic anhydride) each formedthree principal adducts in DNA. Adduct 1 of IQ, MeIQx and PhlPwas chromatographically identical to the 32P-labeled bis(phosphate)derivative of N-(deoxyguanosin-8-yI)-IQ, N-(deoxyguanosin-8-yI)-MeIQx,and N-(deoxyguanosin-8-yl)-PhIP respectively, and this adductcomprised  相似文献   

15.
Mixtures of creatinine, glucose and various single amino acidswere heated at 180°C for 10 min in an aqueous model system.The heated mixtures all showed mutagenic activity, ranging from80 to 2400 TA98 revertant colonies/µmol creatinine withmetabolic activation. Testing of HPLC fractions for mutagenicactivity showed each mixture to contain several mutagenic components,some of which corresponded to known heterocyclic amines andothers to unknown compounds. The presence of 2-amino-3-methyl-imidazo[4,5-f]quinoxaline,2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline and 2-amino-3,7,8-trimethylimidazo[4,5-f]quinoxalinein most of the samples was established using HPLC with photodiodearray detection and liquid chromatography/mass spectrometrywith electrospray interface and single ion monitoring. In addition,2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine,3-amino-1,4-di-methyl-5H-pyrido[4,3-b]indole and 3-amino-1-methyl-5H-pyrido[4,3-b]indoleand the co-mutagenic compounds 9H-pyrido[3,4-bindole and 1-methyl-9H-pyrido[3,4-b]indolewere detected in some samples.  相似文献   

16.
The carcinogenic heterocyclic amine 2-amino-3,8-dimethyl-imidazo[4,5-f]quinoxaline(MeIQx) is widely distributed in cooked foods. The nucleaseP1 method increased the sensitivity of the standard 32P-postlabelinganalysis about 1000-fold for detection of MeIQx-DNA adducts.The recovery of MeIQx-DNA adducts by the nuclease P1 methodwas determined to be about 50% using liver DNA of a rat treatedwith [14C]MeIQx intragastrically. By the nuclease P1 methodfive adducts were detected in the liver DNA of rats fed MeIQxand two of them, including the most abundant one, were identifiedas MeIQx-deoxyguanosine adducts by comparison with the adductsformed in in vitro reactions of N-acetoxy-2-amino-3,8-dimethylimidazo[4,5-f)quinoxalinewith the four 2'-deoxyribonucleotides. The most abundant adductin vivo was identified as N2-(deoxyguanosin-8-yl)-MeIQx 3',5'-diphosphate(3',5'-pdGp-C8-MeIQx). MeIQx-DNA adduct levels in human tissuescould be determined by the nuclease P1 modification of the 32P-postlabelingmethod in combination with HPLC, and thus provide informationon the roles of MeIQx in human carcinogenesis.  相似文献   

17.
Aeschbacher  H.U.; Ruch  E. 《Carcinogenesis》1989,10(3):429-431
Two of the major bacterial mutagens formed in heated meat products,2-amino-3-methylimidazo[4, 5-f]quinoline and 2-amino-3, 8-dimethylimidazo[4,5-f quinoxaline or the basic fraction of beef extract induceda low frequency of sister chromatid exchanges in human lymphocytecultures in the presence of metabolic activation. Structuralchromosome aberrations were not induced at comparable high concentrationsin human lymphocytes with intact repair system, suggesting thatrepair or induction of point mutations are involved in the DNA-damagingeffect of heterocyclic amines rather than structural chromosomeaberrations. Accordingly it may be concluded that mammaliancells with both intact repair and enzyme systems are more relevantthan bacterial systems for evaluating the carcinogenic potentialof heterocyclic amines.  相似文献   

18.
Cooked meat, poultry and fish contain a number of mutagenicand carcinogenic heterocyclic amines, including 2-amino-3-methylimidazo[4,5-f]quinoline(IQ), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx)and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP).In the present study we examined the capacity of hepatic microsomesfrom Fischer 344 rats, cynomolgus monkeys and humans to metabolicallyactivate IQ, MeIQx and PhIP in vitro using the Ames Salmonellamutagenicity assay. The mutagenic activation of IQ was similaramong the three species; however, there were significant differencesamong the species in the activation of PhIP and MeIQx. Livermicrosomes from humans showed the greatest capacity to activatePhIP and MeIQx, followed by rats, and then monkeys. The largestdifferences between the species were observed when MeIQx wasused as the mutagen. MeIQx–DNA adducts formed in vivowere then compared among rats and monkeys given MeIQx by gavage(20 mg/kg/day, 10 doses). 32P-Postlabeling analysis, carriedout under intensification conditions, was used to examine MeIQx–DNAadducts in the liver, kidney, heart, colon and white blood cells.MeIQx–DNA adducts were highest in all tissues examinedfrom male rats, followed by female rats, and much lower in monkeys.In the liver, the total MeIQx–DNA adduct levels of monkeyswere {small tilde}19 and {small tilde}10 times lower than inmale and female rats respectively. In extrahepatic tissues,the differences in MeIQx–DNA adduct levels between monkeysand rats were even greater. The results suggest that the lowlevel of MeIQx–DNA adducts found in vivo in cynomolgusmonkeys reflects a low capacity to activate MeIQx via the hepaticcytochrome P450 monooxygenase system.  相似文献   

19.
An investigation was undertaken to study DNA replication incultured human HeLa cells and Esclze,ichia coli in responseto nickel chloride (NiCl2) Treatment with NiCl2 increased boththe rate of DNA replication and total cell number in HeLa cellsand E.coli in a time- and concentration-dependent manner. Themaximum stimulation of thymidine uptake into DNA was observedwith 0.125—0.25 mM NiCl2 for both cell types. In studiesof DNA replication using a crude HeLa cellular extract, NiCl2at concentrations below 0.125 mM also induced a stimulationover the background of MgCl2 [3H]dTMP incorporation into activatedcalf thymus DNA. However, a similar sthnulatory effect fromNiCl2 was not observed with either purified HeLa DNA polymerasea or E.coli DNA potymerase I Klenow fragment. In the absenceof Mg2 +,the low response of either DNA polymerase a or Klenowfragment to stimulation by Ni2+ was thought to be enhanced bythe presence of Ni2 binding proteins presented In the crudeHeLa cell extract.  相似文献   

20.
Electron paramagnetic resonance and electronic absorption spectroscopieshave shown that unlike the bidentate Cr(V) complex [Cr(ehba)2O](ehba = 2-hydroxy-2-ethylbutanoato(2—)), I, the macrocyclictetradentate complex, [Cr (mampa-dcb)(O)] (mampa-dcb= 5,6-(4,5-dichlorobenzo)-3,8,11,13-tetraoxo-2,2,9,9-tetramethyl-12,12-diethyl-1,4,7,10-tetraazacyclotridecane),II, is substitutionally inert. Low levels of DNA strand cleavagewere observed after treatment with II under physiological conditions(50 mM sodium phosphate, pH 7.4, 37°C) at concentrationsas high as 2 mM for periods as long as 2 days. II also inducesa lower number of revertants in mutation assays with Salmonellatyphimurium TA100 than I when identical Cr concentrations areapplied. The slopes of the linear portion of the dose—responsecurves are parallel, however, indicating that the mutagenicityof II is comparable to I. II is stable toward ligand exchange,reduction and disproportionation in the mutagenicity test mediumand also in the presence of bacteria and the common cell reductant,glutathione. This indicates that ligand exchange with DNA and/orreduction to Cr(IV) are not responsible for the mutagenicityof II (unlike I). It is believed that II reversibly but weaklyintercalates with DNA placing the Cr(V) center in close proximityfor hydrogen atom abstraction or oxo-transfer reactions to ensue.This tetraamide complex is a good structural and biomimeticmodel for non-sulfur-containing Cr(V) peptide species that mayform in vivo from reactions of Cr(VI) with peptides. Hence,it is likely to be relevant to understanding one possible mechanismby which Cr(VI) causes cancer.  相似文献   

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