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1.
Although benzidine (Bz), 4-aminobiphenyl (ABP), 3,3′-dichlorobenzidine HCl (DCBz), 3,3′-dimethylbenzidine (DMBz), 3,3′-dimethoxybenzidine (DMOBz) and the benzidine congener-based dye trypan blue (TB) produce primarily frameshift mutations in Salmonella typhimurium, the base-substitution strain TA100 also responds to these compounds when S9 is present. Performing DNA sequence analysis, other investigators have shown that ABP induces frameshift, base-pair and complex mutations. Also, it was found that an uninduced hamster liver S9 preparation with glucose-6-phosphate dehydrogenase, FMN, NADH and four times glucose 6-phosphate gave a stronger mutagenic response than the conventional plate incorporation with rat S9 activation mixture for all the compounds tested. Using the base-specific tester strains of S. typhimurium (TA7001–TA7006) with the above reductive metabolic activation system, we surveyed these compounds for the ability to produce specific base-pair substitutions after reductive metabolism. Bz was weakly mutagenic in TA7005 (0.04 revertants/μg). ABP was mutagenic in TA7002 (1.4 revertants/μg), TA7004 (0.6 revertants/μg), TA7005 (2.98 revertants/μg) and TA7006 (0.4 revertants/μg). DCBz was weakly mutagenic in TA7004 (0.01 revertants/μg). It was concluded that benzidine induced some CG->AT transversions in addition to frameshift mutations. ABP induced TA->AT, CG->AT, and CG->GC transversions as well as GC->AT transitions. DCBz induced only GC->AT transitions. Because DMBz, DMOBz and TB were not mutagenic in this base-substitution mutagen detection system, their mutagenic activity was attributed strictly to frameshift mechanisms. 相似文献
2.
The azo dye tartrazine, after dosing by gavage, is transformed by rats into urinary metabolites which exert dose-dependent mutagenic activities in the Ames test with Salmonella typhimurium TA 98 after addition of rat liver metabolizing enzymes (S9 mix). The strain TA 100 showed no mutagenic response.
Abbreviation: FD & C Yellow No. 5 (5-oxo-1-(p-sulphophenyl)-4-(sulphophenylazo)-2-pyrazoline-3-carboxylic acid, trisodium salt) 相似文献
3.
Although benzidine (Bz), 4-aminobiphenyl (ABP), 3,3′-dichlorobenzidine HCl (DCBz), 3,3′-dimethylbenzidine (DMBz), 3,3′-dimethoxybenzidine (DMOBz) and the benzidine congener-based dye trypan blue (TB) produce primarily frameshift mutations in Salmonella typhimurium, the base-substitution strain TA100 also responds to these compounds when S9 is present. Performing DNA sequence analysis, other investigators have shown that ABP induces frameshift, base-pair and complex mutations. Also, it was found that an uninduced hamster liver S9 preparation with glucose-6-phosphate dehydrogenase, FMN, NADH and four times glucose 6-phosphate gave a stronger mutagenic response than the conventional plate incorporation with rat S9 activation mixture for all the compounds tested. Using the base-specific tester strains of S. typhimurium (TA7001–TA7006) with the above reductive metabolic activation system, we surveyed these compounds for the ability to produce specific base-pair substitutions after reductive metabolism. Bz was weakly mutagenic in TA7005 (0.04 revertants/μg). ABP was mutagenic in TA7002 (1.4 revertants/μg), TA7004 (0.6 revertants/μg), TA7005 (2.98 revertants/μg) and TA7006 (0.4 revertants/μg). DCBz was weakly mutagenic in TA7004 (0.01 revertants/μg). It was concluded that benzidine induced some CG->AT transversions in addition to frameshift mutations. ABP induced TA->AT, CG->AT, and CG->GC transversions as well as GC->AT transitions. DCBz induced only GC->AT transitions. Because DMBz, DMOBz and TB were not mutagenic in this base-substitution mutagen detection system, their mutagenic activity was attributed strictly to frameshift mechanisms. 相似文献
4.
The aim of this study was to determine the potential toxic effects of iron(II,III)oxide nanoparticles (IONPs). In in vivo experiments, the toxic effects of IONPs were monitored in adult male Wistar rats by morphological methods after a single intratracheal instillation. For the control group 1 ml of physiological saline per animal was given, and the treatment group received the same volume of a suspension containing 1 and 5 mg kg?1 body weight IONPs. Lungs and internal organs underwent histopathological examination after 1, 3, 7, 14 and 30 days. The mutagenic effect of these nanoparticles was evaluated by the bacterial reverse mutation assay on Salmonella typhimurium TA98, TA100, TA1535 and TA1537 strains, and on Escherichia coli WP2uvrA strain, in the presence and absence of the mammalian metabolic activation system S9. The in vitro cytotoxic effect of IONPs was also examined in Vero cells after short‐term (4 h) and long‐term (24 h) exposure. There were no pathological changes in examined internal organs, except a very weak pulmonary fibrosis developing by the end of the first month in the treated rats. While in vitro MTT assay showed a moderate cytotoxic effect, IONPs proved to be devoid of mutagenic effect in the bacterial systems tested. The results may be a useful extension of our knowledge on the safety of magnetite nanoparticles in view of their possible medical applications, such as in hyperthermia and magnetic resonance imaging. Copyright © 2011 John Wiley & Sons, Ltd. 相似文献
5.
Rohan M. Kulkarni Emily W. Dakoulas Ken E. Miller 《Toxicology mechanisms and methods》2017,27(7):518-527
DON (6-diazo-5-oxo-l-norleucine), a glutamine antagonist, was demonstrated to exhibit analgesic, antibacterial, antiviral and anticancer properties. The study was performed to characterize its in vitro and in vivo genetic toxicity potential. DON was tested in the bacterial reverse mutation assay (Ames test) using Salmonella typhimurium tester strains (TA98, TA100, TA1535 and TA1537) and Escherichia coli tester strain (WP2 uvrA) with and without S9 and also with reductive S9. In addition, DON was tested for the chromosome aberrations in Chinese hamster ovary (CHO) cells with or without S9 to evaluate the clastogenic potential. Furthermore, DON was also evaluated for its in vivo clastogenic activity by detecting micronuclei in polychromatic erythrocyte (PCE) cells in bone marrow collected from the male mice dosed intravenously with 500, 100, 10, 1 and 0.1?mg/kg at 24 and 48-h post-dose. The Ames mutagenicity assay showed no positive mutagenic responses. However, the in vitro chromosome aberration assay demonstrated dose dependent statistically positive increase in structural aberrations at 4 and 20-h exposure without S9 and also at 4-h exposure with S9. The in vivo micronucleus assay also revealed a statistically positive response for micronucleus formation at 500, 100 and 10?mg/kg at 24 and 48-h post-dose. Thus, DON appears to be negative in the Ames test but positive in the in vitro chromosome aberration assay and in the in vivo micronucleus assay. In conclusion, the results indicate DON is a genotoxic compound with a plausible epigenetic mechanism. 相似文献
6.
Y. W. Kim Y. K. Kim J. Y. Lee K. T. Chang H. J. Lee D.-K. Kim 《Xenobiotica; the fate of foreign compounds in biological systems》2013,43(3):325-339
The authors investigated the pharmacokinetics and metabolism of 3-((5-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)benzamide (IN-1130), a novel ALK5 inhibitor, which suppresses renal and hepatic fibrosis, and also exerts anti-metastatic effects on breast cancer-bearing MMTV-cNeu mice model. Plasma half-lives of orally administered IN-1130 were 62.6 min in mice, 76.6?±?10.6 min in dogs, 156.1?±?19.3 min in rats, and 159.9?±?59.9 min in monkeys. IN-1130 showed a high apparent permeability coefficient (Papp) of (45.0?±?2.3)?×?10?6 cm s?1 in in vitro permeability tests in a Caco-2 cell monolayer model. The bioavailability of orally administered IN-1130 was 84.9% in dogs and 34.4% in monkeys (oral dose, 5.5 mg kg?1), 11.4% in rats and 8.95% in mice (oral dose, 50.3 mg kg?1), respectively. Orally given IN-1130 was readily distributed into liver, kidneys and lungs. The major metabolite of IN-1130 (M1) was detected in the systemic circulation of rat and mouse and was purified and tentatively identified as 3-((4-(3-hydroxyquinoxaline-6-yl)-5-(6-methylpyridine-2-yl)-1H-imidazol-2-yl)methyl)benzamide or 3-((4-(2-hydroxyquinoxalin-6-yl)-5-(6-methylpyridine-2-yl)-1H-imidazol-2-yl)methyl)benzamide. The highest levels of M1 were found in liver. The results of this study suggest that IN-1130 has the potential to serve as an effective oral anti-fibrotic drug. 相似文献
7.
左旋黄皮酰胺在大鼠体内的排泄 总被引:1,自引:0,他引:1
左旋黄皮酰胺[(-)-clausenamide]是从芸香科黄皮属植物黄皮[Clausena lansium(lour) sheels]叶的水浸膏中分离得到的有效成分,经不对称合成和拆分制备而得。药效学研究表明,左旋黄皮酰胺促进突触体谷氨酸释放,增加大鼠脑皮层厚度和海马CAL区突触数及NMDA受体密度,提高小鼠脑皮层和海马的胆碱乙酰转移酶活性,对抗樟柳碱引起的乙酰胆碱含量降低。这些结果表明左旋黄皮酰胺具有较好的促智和神经保护作用以及潜在的抗老年痴呆作用;右旋体作用不明显,且有较强的毒性。 相似文献
8.
Maria J. Mokrosz Lucjan Strekowski Wei Xing Kozak Beata Duszyska Andrzej J. Bojarski Aleksandra Kodzinska Agnieszka Czarny Marek T. Cega Anna Dere-Wesoek Ewa Chojnacka-Wjcik Stefan Dove Jerzy L. Mokrosz 《Archiv der Pharmazie》1995,328(9):659-666
A series of new 4,6-di(heteroaryl)pyrimidines containing an N-methylpiperazino group ( 6 – 13 ) or an ethylenediamine chain ( 15 – 20 ) in position 2 were synthesized and their 5-HT1A and 5-HT2A receptor affinities were determined. It was shown that the substituent effects on the 5-HT2A affinity are additive and could be described quantitatively. In a behavioral model it was also demonstrated that 6 – 11 are 5-HT2A receptor antagonists. The molecular modelling results suggested that the distances between the basic nitrogen atom and the two aromatic centers (d1 = 5.2?8.4 Å, d2 = 5.7?8.5 Å, and d3 = 4.6?7.3 Å) define the molecular topography of the 5-HT2A receptor antagonists under study. 相似文献
9.
Praziquantel, a new anthelmintic drug with activity against all species of schistosomes pathogenic to man, and against a wide range of Cestodes, was tested for mutagenic potential. For the detection of both base substitutions and frameshift mutations, Salmonella typhimurium TA 100 and TA 98 were used as tester strains. Using the plate assay with and without added S-9, host-mediated assay and urine-mediated assay without and after incubation with -glucuronidase/arylsulfatase, no mutagenic activity could be detected. 相似文献
10.
Six chemicals used as ingredients in cosmetics were evaluated for mutagenic activity in Salmonella typhimurium. Two of these ingredients, trans-4-phenyl-3-butene-2-one and 2,2′,4,4′-tetrahydroxybenzophenone, were mutagenic in the presence of rat liver S-9 towards strains TA100 and TA1537 respectively. An impurity found in some cosmetic products, N-nitrosodiethanolamine, was mutagenic to S. typhimurium stains TA1535 and TA100 in the presence of hamster-liver S-9 but not rat-liver S-9. 相似文献
11.
Abstract: The inhibitory activities of a number of compounds on the simultaneous uptake of 3H-dopamine (3H-DA) and 14C-5-hydroxytryptamine (14C-5-HT) in the same slices of the mouse striatum were examined. Experiments with inactive DA and 5-HT demonstrated that the uptake of the two amines occurs at different sites. In vitro (+)-amphetamine was 2.7 times more potent than the (-)-isomer whereas in vivo this difference was about 6 times. (+)-Amphetamine was also significantly more active than the (-)-enantiomer on the 3H-DA uptake in striatal slices from the rat. The methylester group in cocaine is essential for the inhibitory activity of cocaine, which had similar potencies on the two uptake mechanisms. Benztropine was much more active on the 3H-DA uptake than on the 14C-5-HT uptake. In vivo the amphetamine derivatives including prolintane and methylphenidate were the most active compounds on the 3H-DA uptake, but the 4-substituted amphetamines were more active on the 14C-5-HT uptake. Among other compounds benztropine was as active as (+)-amphetamine on the 3H-DA uptake. None of the compounds tested seem to be useful as model compounds for the selective inhibition of the DA uptake, since they have other pharmacological effects at lower doses. 相似文献
12.
《Journal of applied toxicology : JAT》2017,37(9):1125-1128
Next‐generation sequencing (NGS) is a potentially useful technology to achieve a more precise evaluation of chemical mutagenicity. To establish NGS‐based mutagenicity assays, which enable the direct detection of chemically induced mutations in a whole genome manner, the selection of appropriate biological resources and their precise genome sequences are essential. Here, we performed genome re‐sequencing analyses of Salmonella typhimurium LT‐2 strains TA98 and TA100, which have been frequently used in mutagenicity assays. We identified several strain‐specific mutations including those that were relevant to their known phenotypes (his , ΔuvrB and rfa ). The details of rfa mutations were first clarified in this study, which was a frameshift variant in rfaF and a missense variant in rfaC in TA98 and TA100, respectively. The uvrB deletion in TA98 was larger than that in TA100, which suggested differences in defects of lipopolysaccharide synthesis between these strains. The re‐sequenced genome data of TA98 and TA100 will help us establish NGS‐based bacterial mutagenicity assays and understand the biological events seen in them. Copyright © 2017 John Wiley & Sons, Ltd. 相似文献
13.
《Drug and chemical toxicology》2013,36(4):245-257
AbstractSome 2-substituted-1H-phenanthro [9,10-d] imidazole compounds synthesized as a predrugs were tested in mutagenicity assays in Salmonella strains TA97, TA98, and TA100 using a plate incorporation assay both with and without S9 mix. The 10 substances were mutagenic in TA97 and five of them were mutagenic only with metabolic activation, whereas one of them did not require the addition of S9. The eight substances were mutagenic in TA98 only with S9. For TA100, seven substances showed positive results both with and without S9, however another four required S9, whereas only one of them did not required metabolic activation. In summary, all of 13 substances derived from phenanthro [9,10-d] imidazole were found to be mutagenic for at least one or two of the three strains and their mutagenicity are discussed. 相似文献
14.
15.
Afef Abdelwahed Ines Skandrani Soumaya Kilani A. Neffati Mohamed Ben Sghaier Ines Bouhlel 《Drug and chemical toxicology》2013,36(1):37-60
Mutagenic and antimutagenic activities against direct acting mutagens, nifuroxazide (NF) and sodium azide (SA), and indirect acting mutagen aflatoxin B1 (AFB1) of extracts prepared from aerial parts of Pituranthos tortuosus were investigated in bacterial assay systems (i.e., the Ames test with Salmonella typhimurium TA100, TA98, TA1538, TA1535, and the SOS chromotest with Escherichia coli PQ 37). It was found that all extracts obtained from P. tortuosus decreased the mutagenicity induced by AFB1 (10 μg/assay), SA (1.5 μg/assay), and NF (20 μg/assay). Ethyl acetate, acetone, methanol, and total oligomer flavenoid extracts exhibited the highest inhibition level of mutagenicity induced by the indirect mutagen AFB1. In addition, antiproliferative and apoptotic properties of these extracts have also been reported using two leukemia cell lines, L1210 and K562. The results revealed that all extracts showed a significant cytotoxic effect on these cell lines, and the effect was greater in the presence of human K562 chronic myelogenous leukemia cells, whereas they do not induce apoptosis. 相似文献
16.
Yu Luo Ling Qiu Yun Deng Xiao-Hong Yuan Ping Gao 《Journal of Asian natural products research》2013,15(9):883-888
AbstractA new chromone and a new aliphatic ester were isolated from the EtOAc extract of myceliums of Daldinia eschscholtzii. Their structures were elucidated as (R)-5-hydroxy-8-methoxy-2-methylchroman-4-one (1) and (E)-6-(non-3-en-1-yl) -2H-pyran-2-one (2) by interpretation of the spectroscopic evidence. 相似文献
17.
Takenaka Osamu Horie Toru Kobayashi Kazuo Suzuki Hiroshi Sugiyama Yuichi 《Pharmaceutical research》1995,12(11):1746-1755
Purpose. Previously, we found that the biliary excretion of the 6-hydroxy-5,7-dimethyl-2-methylamino-4-(3-pyridylmethyl) benzothiazole (E3040) glucuronide is severely impaired in Eisai hyperbilirubinemic rats (EHBR), while that of sulfate remains normal (Takenaka et al., J. Pharmacol. Exp. Then, 274: 1362–1369, 1995). The purpose of the present study is to clarify the mechanisms for impairment of the biliary excretion of E3040 glucuronide in EHBR.
Methods. We kinetically analyzed the disposition of the conjugates in the perfused liver at steady state. The uptake of the conjugates into the isolated canalicular membrane vesicles (CMVs) was also examined.
Results. At steady state, the bile/liver unbound concentration ratios of the conjugates were 40-400 in both rat strains, indicating a highly concentrated process. The biliary excretion clearance (CLu,bile) of the glucuronide, defined for the unbound concentration in the liver, was decreased in EHBR to 1/30 of that in normal rats, whereas the CLu,bile of the sulfate was comparable between the two rat strains. In vitro, the transport of E3040 glucuronide into CMV prepared from SD rats exhibited the ATP dependency, whereas minimal effect of ATP was observed on the uptake of the glucuronide into CMV from EHBR. In contrast, the uptake of E3040 sulfate was comparable between SD rats and EHBR. Furthermore, ATP did not stimulate the uptake of sulfate into the CMVs.
Conclusions. It was suggested (1) that the excretion of E3040 glucuronide across the bile canalicular membrane is mediated by the primary active transporter which is defective in EHBR and (2) that the bile canalicular transport system for E3040 sulfate is different from that for the glucuronide in that the former remains normal in EHBR. 相似文献
18.
Erik J. Sderlund Sidney D. Nelson Erik Dybing 《Basic & clinical pharmacology & toxicology》1979,45(2):112-121
Abstract The flame retardant tris(2,3-dibromopropyl)phosphate (Tris-BP) is converted to products which are mutagenic for Salmonella typhimurium TA 100 in the presence of rat liver microsomes, NADPH and oxygen. Other bromopropyl-compounds were also mutagenic; 2,3-dibromopropene and 2,3-dibromopropionic acid were directly mutagenic, whereas 2,3-dibromopropanol and tris(2-bromopropyl)phosphate were weakly mutagenic after addition of liver microsomes and cofactors. Typical in vivo and in vitro inhibitors of cytochrome P-450 inhibited Tris-BP mutagenicity. The effects of inducers of cytochrome P-450 on Tris-BP mutagenicity was dependent on the concentration of mutagen and microsomal protein in the assay, indicating complexity in the kinetics involved when dealing with possible multiple pathways that lead to mutagenicity. Addition of glutathione strongly inhibited Tris-BP mutagenicity. It is suggested that Tris-BP is oxidized to a reactive electrophile, possibly the 2-keto derivative, which could react with nucleophilic groups in DNA and thus lead to mutagenic events. 相似文献
19.
According to the principle of isosterism the-CH2-group of 5-(substituted benzyl)-2, 4-diaminopyrimidine was modified by—S—and—Se—and some 5-(substituted phenyl)thio-2, 4-diaminopyrimidines and 5-(substituted phenyl)seleno-2,4-diaminopyrimidines were synthesized. Their inhibitory activities on L. casei and chicken liver dihydrofolate reductase were determined. Preliminary data showed that the inhibitory activities of these compounds were less than those of the corresponding 5-(substituted benzyl)-2, 4-diaminopyrimidines. Their selectivities are also decreased. 相似文献