Mutagenicity studies

An antiulcer drug, 4-(2-carboxyethyl) phenyl trans 4-aminomethylcyclohexane carboxylate hydrochloride (DV-1006), was studied for mutagenicity using bacterial systems, in vitro and in vivo cytogenetics, and dominant lethal tests.No mutagenicity of DV-1006 was observed either in the rec-assay on Bacillus subtilis or in the Salmonella/microsome test (Ames test). In in vitro cytogenetics, DV-1006 had no effects on the chromosomes of Chinese hamster cells at cytotoxic doses. Rats were treated singly or on 5 consecutive days orally with dose levels of 16, 160, or 1600 mg DV-1006/kg for detecting cytogenetic effects in vivo. As a result, no increase of the incidence of chromosomal aberrations in bone marrow cells was observed in any group of DV-1006. A single or 5 daily oral administration of DV-1006 (16 or 1600 mg/kg) to male mice and subsequent mating for 8 weeks produced no dominant lethal mutational effects. These results show that DV-1006 has no mutagenic potential.     

Mutagenicity of para-nitroso-dimethyl- and diethyl-anilines

Low concentrations of para-nitroso-dimethylaniline (NdMA) were mutagenic to Salmonella typhimurium TA100 with optimal effect at 1.5 microM in fluctuation assays, without activating enzymes. The diethyl homologue (NdEA) had little or no mutagenic effect at low concentrations, although the bacteriocidal effects of NdMA and NdEA were similar. At higher bacteriocidal concentrations (approximately LC55-LC80) both NdMA and NdEA were mutagenic. NdMA and some other C-nitroso compounds proved carcinogenic in animal bioassays, and further research is needed to assess the human hazard from exposure to C-nitroso compounds in food, medicines or industry.     

Mutagenicity of proanthocyanidins

Several procyanidins with different degrees of polymerization (dimers, a trimer and a polymer) and extracted from different natural sources were found to be non-mutagenic in the Salmonella mutagenesis assay system. A mutagenic impurity in procyanidin B-4 was isolated by means of reversed-phase high-performance liquid chromatography (HPLC) and identified as rutin with UV spectrometry, co-chromatography on reversed-phase HPLC and gas chromatography-mass spectrometry.     

Mutagenicity of 3-methylcholanthrene, pcb3, and 4-oh-pcb3 in the lung of transgenic bigblue rats

Recent findings of high levels of predominantly lower chlorinated biphenyls in indoor and outdoor air open the question of possible health consequences. Lower chlorinated biphenyls are more readily metabolized to reactive and potentially harmful intermediates, acting as mutagens and cancer initiators. The goal of this study was to assess the mutagenicity of PCB3 in the lungs of rats. Male BigBlue? 334 Fisher transgenic rats, which carry the bacterial lacI gene as a target of mutagenicity, were given intraperitoneal injections of corn oil, 3-methylcholanthrene (3-MC, positive control), 4-monochlorobiphenyl (PCB3) or its metabolite 4-hydroxy-PCB3 (4-OH-PCB3) weekly for 4 weeks. Lungs tissue was harvested to determine mutant frequencies, mutation spectra, and pathological changes. 3-MC caused a 15-fold increase in mutant frequency and an increase in transversion type mutations; a very early occurrence of this type of mutation in lung tissue was previously identified in Ki-ras oncogenes of lung tumors from 3-MC exposed mice. The 2-fold increase in the mutant frequency after treatment with PCB3 and 4-OH-PCB3 was not statistically significant, but a shift in the mutation spectra, especially with PCB3, and an increase in mutations outside of the hotspot region for spontaneous mutations (bp 1-400), suggest that PCB3 and possibly 4-OH-PCB3 are mutagenic in the rat lung.     

抗癌新药——去甲斑蟊素致突变的系列研究

作者近年按国际标准建立了药物短期致突变系列,这一系列包括用于测定基因(点)突变的Ames试验和测定染色体畸变的中国仓鼠肺细胞试验及微核试验。应用这一系列评价了我国创制的抗癌新药——去甲斑蟊素的致突变性.测试系统还将Ames新菌株、CHL-ED_(50)剂量法则、NIH敏感品系小鼠应用于这一系列。实验显示去甲斑蟊素既不诱发基因(点)突变,也不诱发染色体畸变,这是去甲斑蟊素与一般抗肿瘤制剂之不同点.     

Mutagenicity and carcinogenicity of environmental chemicals

This article presents a brief analysis of the qualitative relationship between carcinogenicity and mutagenicity (DNA-damaging activity), based on chemicals which are known to be or suspected of being carcinogenic to humans and/or to experimental animals. Details have been published elsewhere (Tomatis et al., 1982; Bartsch et al., 1982).     

Mutagenicity and cytotoxicity tests of garlic

Mutagenicity and cytotoxicity of fresh juice and alcohol extract from garlic were studied by Ames' test, Rec assay, Micronucleus test and the check of the influence to HEp 2 and chinese hamster embryo (CHE) primary cultured cells. No evidence of mutagenicity of these samples were observed in Ames' test and Rec assay, while there was dose dependent increase of micronucleated cells and polychromatocytes on the bone marrow cells of mice and chinese hamsters treated with garlic juice. There were severe damages, e.g. growth inhibition and morphological changes of both cultured cells due to garlic juice, but no or slightly cytotoxic signs were observed even in high concentration of garlic extract. A higher sensitivity to the cytotoxic effects of garlic was seen by the present findings with CHE primary cells than HEp 2 cell line.     

Mutagenicity of acrylonitrile.

Incubation of Salmonella typhimurium strains in an atmosphere of 0.2% gaseous acrylonitrile increased the numbers of his+ revertants/plate only in the presence of a fortified S9 liver fraction. The mutagenic effect was particularly pronounced with strains TA1530, TA1535 and TA1950 and much weaker with strains TA100, TA98 and TA1978. The results of bacterial fluctuation tests confirmed the necessity of the presence of S9 mix and showed the particular sensitivity of TA1530. The reversion rate varied with the S9 mix composition, the animal species utilized and the type of pretreatments applied to the animals. The mutagenicity of acrylonitrile in S. typhimurium is therefore microsome-mediated and is particularly discernable with strains sensitive to base-substitution mutagens.     

Mutagenicity of 2-hydroxyalkyl-N-nitrosothiazolidines

The mutagenicity of 2-hydroxyalkyl-N- nitrosothiazolidines was tested using Salmonella typhimurium strains TA98 and TA100. The N- nitrosothiazolidines tested were unsubstituted N- nitrosothiazolidine (NT), N- nitrosothiazolidine -4-carboxylic acid ( NTC ), 2-hydroxymethyl-N- nitrosothiazolidine ( HMNT ), 2-(1,2,3,4- tetrahydroxybutyl )-N- nitrosothiazolidine , 2-(1,2,3,4- tetrahydroxypentyl )-N- nitrosothiazolidine , 2-(1,2,3,4,5- pentahydroxypentyl )-N- nitrosothiazolidine ( PHPNT ) and 2-(1,2,3,4,5- pentahydroxypentyl )-N- nitrosothiazolidine -4-car boxylic acid. Among the N- nitrosothiazolidines tested, only HMNT and PHPNT exhibited clear dose-response mutagenicity toward strain TA100 with or without metabolic activation. None of the 2-hydroxyalkyl-N- nitrosothiazolidines were mutagenic to strain TA98. NT exhibited much stronger mutagenicity than either HMNT or PHPNT . Mutagenic activities of NT and PHPNT were eliminated by carboxyl substitution in the position alpha to the N-nitroso group.     

Mutagenicity studies of miporamicin

Mutagenic activity of miporamicin (MPM), a new macrolide antibiotic for animal use, was examined using the reversion test with bacteria, the chromosomal aberration test with mammalian cells in culture and the micronucleus test with rodents. In the reversion test, MPM exhibited severe growth inhibition effect on the test bacteria but caused no increase of revertant colonies over the baseline levels, alone or in combination with S 9 mixture. In the chromosome aberration test, MPM induced a medium grade increase of chromosome aberrations at high concentrations, but induced no increase of polyploid cells over the control level. In the micronucleus test, MPM had no effect on induction of micronucleated polychromatic erythrocyte even at the 1/2 LD50 dose. From these results, we concluded that MPM has no effect on the induction of point mutations but has a weak clastogenicity which is detectable only by in vitro tests.     

间苯二酚致畸,致突变研究

间苯二酚对SD大鼠无致胎鼠畸胎作用;Ames试验TA_(98)和TA_(100)加S_9与不加S_9均阴性;大小鼠染色体畸变和微核试验阴性;接触间苯二酚工人淋巴细胞染色体畸变率未增高;人外周血淋巴细胞体外培养染色体畸变率与对照组比较有非常显著的升高。     

Mutagenicity study of Remsen-Fahlberg saccharin and contaminants

Saccharin and contaminants of commercial Remsen-Fahlberg saccharin were studied for mutagenic potential with the use of the Salmonella/microsome test, Basc-test in Drosophila melanogaster and micronucleus test in mice. In none of these tests were mutagenic effects of saccharin observed. Likewise, the ortho- and para-sulfamoylbenzoic acids (OSBA and PSBA) were ineffective. Para-toluenesulfonamide (PTS) and the major contaminant ortho-toluene-sulfonamide (OTS) exhibited weak mutagenic effects in a modified Salmonella/microsome test and in Drosophila. These results do not indicate mutagenic and therewith correlated carcinogenic potential of saccharin, but they emphasize the possible activity of contaminants.     

Mutagenicity of enantiomers of penbutolol

With a view to examine the effect of chirality and the cause of batch-to-batch variation in the mutagenicity of penbutolol, penbutolol enantiomers - isopenbutolol [R(+)-enantiomer] and penbutolol [S(-)-enantiomer] - and two batches of Betapressin were tested employing the Ames Salmonella tester strain TA98. The mutagenic activity of R(+)-enantiomer was found to be similar to that of a batch of penbutolol with a high content of this optical isomer. The pharmaceutical form of penbutolol, Betapressin, exhibited either less or equal mutagenic effectiveness to the S(-)-enantiomer. In the presence of the S9 mix, the mutagenicity of R(+)-enantiomer was only slightly affected in the low dose range of 40 to 160 micrograms/plate. A metabolite of penbutolol, (RS) l"-dehydropenbutolol, did not cause an increase in the number of revertants/plate.     

Mutagenicity of acrolein and acrolein-induced DNA adducts

Acrolein mutagenicity relies on DNA adduct formation. Reaction of acrolein with deoxyguanosine generates α-hydroxy-1, N²-propano-2′-deoxyguanosine (α-HOPdG) and γ-hydroxy-1, N²-propano-2′-deoxyguanosine (γ-HOPdG) adducts. These two DNA adducts behave differently in mutagenicity. γ-HOPdG is the major DNA adduct and it can lead to interstrand DNA-DNA and DNA-peptide/protein cross-links, which may induce strong mutagenicity; however, γ-HOPdG can be repaired by some DNA polymerases complex and lessen its mutagenic effects. α-HOPdG is formed much less than γ-HOPdG, but difficult to be repaired, which contributes to accumulation in vivo. Results of acrolein mutagenicity studies haven’t been confirmed, which is mainly due to the conflicting mutagenicity data of the major acrolein adduct (γ-HOPdG). The minor α-HOPdG is mutagenic in both in vitro and in vivo test systems. The role of α-HOPdG in acrolein mutagenicity needs further investigation. The inconsistent result of acrolein mutagenicity can be attributed, at least partially, to a variety of acrolein-DNA adducts formation and their repair in diverse detection systems. Recent results of detection of acrolein-DNA adduct in human lung tissues and analysis of P53 mutation spectra in acrolein-treated cells may shed some light on mechanisms of acrolein mutagenicity. These aspects are covered in this mini review.     

聚乳酸和乳酸·乙醇酸的致突变性研究

生物降解型高分子化合物聚乳酸(PLA)和乳酸·乙醇酸(PLGA)是作为避孕缓释剂的载体,在体内形成释放系统。近年来,国内外已把生物降解长效避孕药作为寻找新一代长效避孕药物的主攻方向。但是激素避孕药对人体的可能不良影响仍是一个有争议的问题,特别是PLA和PLGA作为一种载体,较长时间包埋在人体组织内,其遗传毒性及细胞毒性等的研究是急待解决的问题。据此,本研究对PLA、PLGA经小鼠微核试验、Ames试验及细胞毒性试验,进行突变性及细胞毒性的评价,为提供安全、有效的避孕药物载体提出科学依据。     

Mutagenicity testing in industry

Summary The aims of authorities, university and industrial scientists are outlined. The prime feature remains: How important are the achieved results for estimating the mutagenic risk to humans?The various methods available for the testing of chemical substances for mutagenicity are compared. Their usefulness to estimate the mutagenic risk are considered and the disadvantages and advantages of such methods are discussed.The industrial toxicologist must apply those methods which permit the most accurate conclusions to be made. Further, the toxicologist has to develop new methods which, based on his own experience are more suitable for making more accurate statements.The results of methods carried out on the germ cell of living mammals permit more accurate statements to be made than investigations on isolated cell cultures and somatic cells. Thus, the dominant lethal test on male and female mice and the spermatogenial test on Chinese hamsters are considered suitable methods for estimating the possible dangers to man.Presented at the 3rd Meeting of the Gesellschaft für Umwelt-Mutationsforschung e. V., D-8042 Neuherberg, July 1–2, 1976