Absence of Mutagenic Activity of Trifluoroethanol and its Metabolites in Salmonella Typhimurium

Absence of Mutagenic Activity of Trifluoroethanol and its Metabolitesin Salmonella Typhimurium. David A. Blake, Maria C. DiBlasiand Gary B. Gordon. (1981). Fundam. Appl. Toxicol. 1:415–418.Trifluoroethanol, trifluoroacetaldehyde and trifluoroacetatewere found to have no mutagenic activity in the standard Salmonellatyphimurium reverse mutation assay (Ames test) using a closedincubation system. Negative results were also obtained whenincubation mixtures included 9000 x g supernatant fractionsof rat liver or testes homogenates along with an NADPH generatingsystem. Rats were pretreated with a polychlorinated biphenylmixture to induce biotransforming enzyme activity. These resultssuggest that the previously reported mutagenic activity of fluroxeneis not due to metabolites arising from the trifluoroethyl sideof the molecule and that inhibition of spermatogenesis in ratsby trifluoroethanol is not mediated through a mutagenic mechanism.     

Absence of Mutagenic Effects of Sodium Dichloroacetate

Sodium dichloroacetate (DCA) is a drug with potential for treatingpatients with stroke and head injury. Conflicting evidence hasbeen published on the mutagenic potential of DCA. A series ofgenetic tests for mutagenicity and clastogenicity was carriedout on pharmaceutical grade DCA. Four types of mutagenicitytest were included, with and without metabolic activation whereappropriate. These studies included: (i) Salmonella and Escherichiacoli mutation (Ames) tests, (ii) thymidine kinase locus forwardmutation in L5178Y mouse lymphoma cells, (iii) tests for chromosomalaberrations in Chinese hamster ovary cells, and (iv) an in vivorat bone marrow erythroid micronucleus test. In each study,there was no evidence of mutagenic activity attributable toDCA. It is possible that the present test material, of pharmaceuticalgrade, has fewer impurities than materials studied in previousreports. These data extend, and in some cases contradict, previouspublished reports on DCA.     

Neuroprotective Activity of Pongamia pinnata in Monosodium Glutamate-induced Neurotoxicity in Rats

This study was designed to evaluate the neuroprotective activity of ethanol extract of Pongamia pinnata stem bark in monosodium glutamate-induced neurotoxicity in rats. Neurotoxicity was induced by intraperitoneal injection of monosodium glutamate 2 g per kg body weight daily for 7 days. Ethanol extract of Pongamia pinnata stem bark (200 and 400 mg/kg) was administered orally after 1 h of monosodium glutamate treatment. Dextromethorphan (30 mg/kg, p.o.) was used as standard drug for the comparison. The degree of protection was determined by various behavioural, locomotor, muscle grip activity, lipid peroxidation and measurement of antioxidant status of glutathione, catalase and superoxide dismutase. Estimation of calcium, sodium and potassium ions in brain tissue and gamma aminobutyric acid level in serum was carried out. The histopathological study of brain tissue was also carried out. Treatment with Pongamia pinnata significantly improved monosodium glutamate-induced alteration in behavioural and locomotor activity and muscle strength. Significant decrease in lipid peroxidation and increase in glutathione, superoxide dismutase and catalase was observed in Pongamia pinnata treated group. Further, Pongamia pinnata also significantly reduced the monosodium glutamate-induced excitotoxicity by decreasing the level of Ca⁺² and Na⁺ with concomitant increase in the level of K⁺. Serum gamma aminobutyric acid level was also increased in Pongamia pinnata treated animals. Further, the histopathological evidence supports the neuroprotective activity of Pongamia pinnata. In conclusion, the present study suggests that the ethanol extract of stem bark of Pongamia pinnata possesses significant neuroprotective activity in albino rats.     

Mutagenic and Leukemogenic Activity of Haloperidol: A Negative Study

ABSTRACT

The mutagenic and leukemogenic potential of haloperidol, a neuroleptic of the butyrophenone class, has been studied in an in vitro Ames Salmonella/microsome test and in an 18-month carcinogenicity study in mice. Three variants of the Salmonella mutation assay were included: the spot test, the standard plate incorporation test and the preincubation test. There was no evidence that haloperidol had any mutagenic activity in any of the Salmonella mutation tests with any of the Salmonella typhimurium tester strains in the presence or absence of Aroclor 1254-induced rat- or mouse-liver S9-mix.

In the 18-month study, haloperidol was injected intraperitoneally as a solution (Haldol^R) at a dosage of 5 mg/kg daily for 5, 10 and 20 consecutive days in 5-week-old mice. Leucocyte counts at several time points and histopathological tumor evaluation 18 months later did not reveal any leukemogenic or other carcinogenic effect. On the basis of these data, it may be concluded that haloperidol is not mutagenic in Salmonella nor leukemogenic in mice.     

Absence of Delayed Neurotoxicity and Increased Plasma Butyrylcholinesterase Activity in Triallate-Treated Hens

Absence of Delayed Neurotoxicity and Increased Plasma ButyrylcholinesteraseActivity in Triallate-Treated Hens. LAPADULA, D. M, JOHANNSEN,F., AND ABOU-DONIA, M. B. (1990). Fundam. Appl. Toxicol. 14,191–198. Triallate (S-2,3,3-trichloroalryl diisopropylthiocarba-mate)was tested for the potential to produce delayed neurotoxicity.Hens were given single oral doses ranging from 312.5 to 2500mg/kg of triallate, 750 mg/kg tri-o-cresyl phosphate (TOCP),or empty gelatin capsules on Days 1 and 21 and were killed onDay 42. In a second experiment, animals were administered dailyoral doses of 25-300 mg/kg triallate or 10 mg/kg TOCP for 90days. In a third experiment, animals were given single oraldoses of 2500 mg/kg triallate, 750 mg/kg TOCP, or empty gelatincapsules and killed after 24 hr. Delayed neurotoxicity was observedonly in TOCP-treated animals. Animals given daily doses of 300mg/kg triallate became moribund after 30 days; however, histologicalexamination revealed no lesions characteristic of organophosphorus-induceddelayed neurotoxicity. Neurotoxic esterase was not significantlyaltered in triallate-treated animals while it was 95% inhibitedin TOCP-treated animals. Plasma butyrylcholinesterase increasedsignificantly 24 hr after treatment with triallate in a dose-dependentmanner. In summary, triallate, a thiocarbamate, did not produceneurotoxicity which has been previously reported for some dithiocarbamates.     

乙双吗啉的致突变作用

目的:研究乙双吗啉的遗传毒性.方法:乙双吗啉5,10和15 mg·kg~(-1),腹腔注射观察诱发的小鼠骨髓染色体/染色单体畸变;应用Ames试验观察对测试菌株TA97,TA98,TA100,TA102的诱变作用.结果:乙双吗啉显著诱发小鼠骨髓染色体/染色单体畸变,其诱发的畸变细胞率(ACF)显著增加(P<0.01);在不加S9条件下,乙双吗啉对TA98,TA102有一定的诱发回复突变的作用.结论:乙双吗啉是一种遗传毒物质.     

Mutagenic determination of passive smoking

The mutagenic activity of tobacco smoke has been further investigated with the plate-incorporation method and a microsuspension technique of the Ames Salmonella assay. The microsuspension test gives a higher response than the conventional plate incorporation test. It is possible to detect environmental tobacco smoke (ETS) in moderately smoky indoor environments by collection of particulate matter with personal low volume samplers followed by particle extraction and mutagenicity testing with the microsuspension assay.     

联苯醛酮的致突性与致畸性研究

联苯醛酮为一具有抗病毒活性的化合物。我们观察它的三种短期致突试验及大鼠致畸胎实验。Ames 试验、小鼠骨髓微核试验及中国仓鼠肺细胞的染色体畸变试验均为阳性。但未见大鼠的胚胎毒性及致畸作用。     

茜素型蒽醌基因突变风险评价

目的 使用毒性预测软件及细菌回复突变（Ames）试验评价茜素型蒽醌的基因突变风险。方法 通过毒性软件Toxtree、Derek Nexus和Sarah Nexus对茜素型蒽醌：茜草素、异茜草素、甲基异茜草素、甲基异茜草素-1-甲醚、茜素-1-甲醚、羟基茜草素、光泽汀进行致突变风险预测;每个受试物设置5个给药浓度,分别在有或无S9代谢活化条件下,使用5种鼠伤寒沙门氏菌TA97、TA100、TA102、TA1535和TA1537开展基于6孔板培养的Ames试验,判断该类化合物苯环上不同取代基对致突变性的影响。结果 软件基于蒽醌环的存在预测该类化合物均具有致突变风险。在非S9代谢活化下,异茜草素和羟基茜草素可导致TA1537回复突变菌落数增加;光泽汀可诱导TA97、TA100和TA1537回复突变菌落数增加。在S9代谢活化下,异茜草素可导致TA97、TA100和TA1537回复突变菌落数增加;羟基茜草素可导致TA1537回复突变菌落数增加;光泽汀可导致TA97、TA100和TA1537回复突变菌落数增加;甲基异茜草素可导致TA97、TA100、TA102和TA1537回复突变菌落数大幅增加;甲基异茜草素-1-甲醚可导致TA100回复突变菌落数增加。结论 茜素型蒽醌受试物在有或无S9代谢条件下表现出不同程度、不同菌株的回复突变,开展相关研究评价其毒性风险对该类化合物合理监管具有重要价值。     

Mutagenic evaluations of two rubber accelerators

Because of evidence of mutagenic activity in certain short-term in vitro assays (unpublished data) N-oxydiethylene thiocarbamyl-N-oxydiethylene sulfenamide (OTOS) and N-oxydiethylene-2-benzothiazole sulfenamide (OBTS) were studied to determine their potential to induce dominant lethal mutations. For 56 consecutive days OTOS (0, 6.25, 12.5, or 25 mg/kg) or OBTS (0, 125, 250, or 500 mg/kg) was administered by gavage to groups of male Sprague-Dawley rats, while the negative control received corn oil. Each male then was mated with two virgin females in each of two successive 1-week periods. A positive control group was given triethylenemelamine (TEM, 0.25 mg/kg) in a single ip dose 1 day prior to mating. A significant depression in body weight gain (24.8%) was observed at the highest dose for OTOS (25 mg/kg). No effect on body weight was noted for OBTS at doses as high as 500 mg/kg. Although sequalae were observed in the OBTS top-dose animals during the test period, none were ascribed clearly to the test material. Similar pregnancy rates (70 to 100%) were observed for the concurrent negative and positive controls and for all test groups of both chemicals. In the TEM controls for both compounds, the number of implantation sites and preimplantation losses were significantly decreased, and the number of early fetal deaths per pregnant female were significantly elevated. However, both OTOS and OBTS failed to produce dominant lethal mutations. The absence of a response emphasized the difficulty in using in vitro and in vivo mutagenic assays as predictors of mutagenesis in man.     

Mutagenic Deimmunization of Diphtheria Toxin for Use in Biologic Drug Development

Background: Targeted toxins require multiple treatments and therefore must be deimmunized. We report a method of protein deimmunization based on the point mutation of highly hydrophilic R, K, D, E, and Q amino acids on the molecular surface of truncated diphtheria-toxin (DT390). Methods: Based on their surface position derived from an X-ray-crystallographic model, residues were chosen for point mutation that were located in prominent positions on the molecular surface and away from the catalytic site. Mice were immunized with a targeted toxin containing either a mutated DT390 containing seven critical point mutations or the non-mutated parental toxin form. Results: Serum analysis revealed a significant 90% reduction in anti-toxin antibodies in mice immunized with the mutant, but not the parental drug form despite multiple immunizations. The experiment was repeated in a second strain of mice with a different MHC-haplotype to address whether point mutation removed T or B cell epitopes. Findings were identical indicating that B cell epitopes were eliminated from DT. The mutant drug form lost only minimal activity in vitro as well as in vivo. Conclusion: These findings indicate that this method may be effective for deimmunizing of other proteins and that discovery of a deimmunized form of DT may lead to the development of more effective targeted toxin.     

京尼平苷对谷氨酸钠诱导性肥胖小鼠的减肥作用研究

目的:研究京尼平苷对L-谷氨酸钠(MSG)诱导性肥胖小鼠的减肥作用。方法:观察京尼平苷对MSG肥胖小鼠体重、Lee氏指数、血糖、血甘油三酯、血胆固醇、脂肪细胞大小的影响。结果:800mg·kg-1剂量下京尼平苷可明显抑制MSG肥胖小鼠的摄食量,减轻体重,降低血甘油三酯、血胆固醇含量,使白色脂肪细胞变小,但对血糖无影响。结论:京尼平苷对MSG肥胖小鼠具有减肥作用。     

伊班膦酸钠注射液的流动注射化学发光法测定

建立了流动注射化学发光法测定伊班膦酸钠.伊班膦酸钠被破坏转化为无机磷,与钼酸铵在酸性条件下形成磷钼杂多酸,与鲁米诺在碱性条件下反应产生化学发光.伊班膦酸钠溶液在5～25 μg/ml浓度范围内线性关系良好.回收率大于97.6％,RSD小于2.0％.     

Evaluation of the Relationship between PAH Content and Mutagenic Activity of Fumes from Roofing and Paving Asphalts and Coal Tar Pitch

Evalution of the Relationship between PAH Content MutagenicAcitivity of Fumes from Roofing and Paving Asphalts and CoalTar Pitch. MACHADO, M. L., BEATTY, P. W., FETZER, J. C., GLICKMAN,A. H., AND McGINNIS, E. L. (1993). Fundam. Appl. Toxicol. 21,492–499. Fume condensates from asphalt and coal tar pitch were evaluatedto determine if polycyclic aromatic hydrocarbon (PAH) composition,crude oil source, or temperature at which the fume was generatedcorrelated with mutagenic activity. The fume condensates weretested for mutagenic activity using a modified Ames Test. Benzo[a]pyrene(BP) and other PAHs were detected in all samples. The concentrationof BP in coal tar pitch was 18, 100 ppm while the concentrationin asphalt was less than 6 ppm. Coal tar fumes contained betweentwo and three orders of magnitude more BP, as well as otherPAH species, than asphalt fumes. Coal tar fume condensates werealso approximately 100 times more mutagenic than those of asphalt.Generation temperature, crude oil source, and/or process conditionsaffected the PAH concentrations but not the mutagenicity inroofing asphalt fume condensates. With paving asphalt fumes,PAH content and mutagenicity varied with crude oil source butnot with processing conditions; due to limited data, it wasnot possible to determine the effect of generation temperature.Coal tar pitch fumes generated at 316°C contained significantlyhigher concentrations of PAHs than those generated at 232°Cand the mutagenic activity generally paralleled the PAH content.A subset of the paving asphalts demonstrated good correlationbetween mutagenicity and three- to seven-ring PAH content. Theseresults indicate that asphalt fumes are far less mutagenic thancoal tar fumes. Asphalt fumes differ in their ability to inducemutagenic activity, and, most likely, in their potential carcinogenicity.     

Mutagenic activity of airborne particulate organic pollutants

Organic extracts of airborne particulates collected at eight urban locations and one nonurban site in Southern California were analyzed for mutagenic activity using Ames' Salmonella typhimurium assay system. All urban samples exhibited mutagenic activity, confirming initial findings. The activity was observed with strains susceptible to frameshift mutation and was not enhanced by the addition of a mammalian metabolic activation system, thus suggesting the presence of mutagens other than benzo(a)pyrene and other polycyclic hydrocarbons which require metabolic activation. Assay of 0.1 to 1 mg of the samples resulted in a 5- to 20-fold increase in his⁺ revertants above the background level, with the number of revertants per plate ranging from 0.10 to 0.44 per μg of organic carbon tested.     

Mutagenic activity of isoniazid in the mouse

Isoniazid was tested for genetic activity in the mammalian spot test by treating in utero mouse embryos, derived from the crosses C57 B1/6J X T-stock and NMRI X DBA/2, heterozygous for various loci affecting coat color. Induction of genetic changes is seen by expression of recessive alleles in colored spots within the fur of the adult animal in a non-agouti background. Injecting mothers with isoniazid (100 mg/kg ip), an expression of recessive loci was found in 7.41% of the F1 animals in the cross C57 B1/6J X T-stock, while in the NMRI X DBA/2 cross 2.92% animals with recessive spots were detected. The control frequencies were respectively 0 and 0.78% animals with recessive spots. The positive control substance, ethyl methanesulfonate (100 mg/kg ip), yielded 5.97% and 4.71% animals carrying a recessive spot in the fur, respectively. These studies clearly demonstrate for the first time the induction of genetic damage other than cytological damage in somatic cells of mice by isoniazid.     

Mutagenic effects of fluphenazine hydrochloride in Drosophila melanogaster

The mutagenic potential of fluphenazine hydrochloride was tested on male germ cells of Drosophila melanogaster. The criterion used was sex-linked recessive lethal mutations. Oregon-K males of D. melanogaster, reared on a medium containing 0.01, 0.02 and 0.03 mg/ml of the drug, were screened for sex-linked recessive lethal mutations. The incidence of sex-linked lethals was significant. The results clearly demonstrate that fluphenazine is capable of inducing recessive lethal mutations in Drosophila especially in pre-meiotic stages of spermatogenesis.