Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: DrugBank:APRD00249 (Mutagen)
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Diethylnitrosamine (DEN) and methylazoxymethanol acetate (MAM) are not transplacental carcinogenic but embryotoxic to Wistar rats when administered by i.p. injection on day 12 of gestation. MAM, a weak teratogen to rats during this period, induced a dose dependent increase in the number of resorptions to 15% and 40% of the litters following doses of 15 and 25 mg/kg bw, respectively. Rats similarly treated with 70, 150, and 180 mg DEN/kg bw resulted in increases in total DNA mass of day 13 embryos by 31%, 45% and 52%, respectively, compared to the saline treated controls. Twenty percent reduction in total DNA amount was detected following 25 mg MAM/kg bw. Benzoylated DEAE-cellulose (BD-cellulose) chromatography fractionates DNA on the basis of secondary structure by stepwise elution of double-stranded DNA with 1.0M NaCl solution (SE-DNA) followed by elution of DNA containing single-stranded regions with caffeine solution (CE-DNA). Day 13 embryonic DNA was monitored by in vivo labelling with [methyl-3H]-thymidine (3H-TdR) on days 6 and 7 of gestation. Significant increases in percentages of caffeine-eluted DNA (%CE-DNA) compared to control values were detected 24 h after treatment of day 12 embryos with 70, 150, and 180 mg DEN/kg bw. Such increases were not observed after MAM. Incorporation of [methyl-14C]-thymidine (14C-TdR) into embryonic DNA demonstrated the effects of treatment with these compounds on DNA synthesis in vivo. When compared to saline controls, DEN induced significant increases in 14C-TdR incorporation into embryo DNA, 1 h prior to analysis, but the increases were not proportional to the doses administered. Similar analysis of MAM treated samples showed no significant changes to %CE-DNA values. The relative %CE-DNA is expressed as the ratio of the percentage of caffeine-eluted 14C-labelled DNA to %CE-DNA (i.e., %CE-14C-DNA:%CE-3H-DNA). In the majority of control embryos the 14C-specific activity of CE-DNA was higher than the 14C-specific activity of SE-DNA. No significant change to relative %CE-DNA values of embryos to those of the controls was observed 24 h after treatment of day 12 gestation rats with single doses of DEN and MAM. The results of this study support the hypothesis that initiation mechanisms of teratogenesis and transplacental carcinogenesis are different. The pertinence of %CE-DNA and relative %CE-DNA values to teratogenesis and transplacental carcinogenesis is also discussed.
Teratog Carcinog Mutagen 1992
PMID:Changes in secondary structure of DNA of rat embryos following treatment with diethylnitrosamine and methylazoxymethanol acetate in vivo. 136 96

Methylazoxymethanol (MAM) is the short-lived toxic and carcinogenic aglycone of cycasin, a natural component of the cycad plant. In the present study, the stable acetate ester of MAM, MAM acetate, was tested in combination with porcine liver esterase and Salmonella typhimurium His G46 to study the comparative mutagenicity of this compound in the presence of rat hepatic alcohol dehydrogenase (ADH), aldehyde dehydrogenase (ALDH), and rat liver microsomes. In the presence of rat liver microsomes and an NADPH-generating system, mutagenicity of MAM acetate was not significantly altered. However, addition of rat liver 105,000g supernatant fraction and/or NAD+ significantly increased the number of his+ revertants above control. A concentration-dependent increase in mutagenicity of MAM acetate was observed for NAD+ from 50 to 200 microM, while NADP+ caused a decrease in mutagenicity of MAM acetate in this same concentration range. Pyrazole (100-500 microM) had no significant effect on mutagenicity of MAM acetate in the presence of rat liver 105,000g supernatant, while disulfiram at 500 microM resulted in a significant decrease in mutagenicity of MAM acetate. The results of this study implicate ALDH as essential in activation of MAM acetate to a mutagenic species in this system, while the role of ADH and microsomes appears to be minimal.
Environ Mol Mutagen 1991
PMID:Mutagenicity of methylazoxymethanol acetate in the presence of alcohol dehydrogenase, aldehyde dehydrogenase, and rat liver microsomes in Salmonella typhimurium His G46. 191 9

The in vitro effects of aneuploidogens on taxol-purified microtubules from whole Drosophila melanogaster and mouse brain were studied by a spectrophotometric assay and electron microscopy. Colchicine, acetonitrile, propionitrile, acrylonitrile, dimethylsulfoxide (DMSO), griseofulvin, and cadmium chloride inhibit microtubule assembly, whereas methoxyethyl acetate (MEA) does not. Qualitatively similar results were observed with D. melanogaster and mouse brain microtubules. The in vitro results from D. melanogaster correlate well with previously published results from in vivo assays monitoring induced sex chromosome aneuploidy in that effective aneuploidogens are observed to affect microtubule assembly. The inclusion of taxol does not appear to qualitatively affect the assembly assays with the chemicals tested. In contrast with results from assembly assays, the tested aneuploidogens, including colchicine, do not promote disassembly to taxol-purified microtubules. It is possible that taxol has shifted the equilibrium and stabilized the formed microtubules to the extent that they are no longer sensitive to aneuploidogen-induced disassembly.
Environ Mol Mutagen 1990
PMID:Aneuploidy in Drosophila. III: Aneuploidogens inhibit in vitro assembly of taxol-purified Drosophila microtubules. 197 71

Quercetin was examined for the effects on the two-stage chemical transformation of BALB/3T3 cells. Quercetin showed initiating action to induce transformation in the cells which were treated with quercetin and subsequently with 0.49 microM 12-O-tetradecanoyl-phorbol-13-acetate (TPA). Both the proportion of dishes with transformed foci and the average number of foci per dish increased with the concentration of quercetin (15-45 microM). However, initiating treatment with quercetin did not induce transformation without subsequent TPA treatment. Quercetin inhibited the promotion caused by 0.49 microM TPA in the transformation initiated by 1.9 microM 2-methylcholanthrene (MCA). The inhibitory effect of 30 microM quercetin was 56% in the number of foci per dish. Thus quercetin was found to have initiating effect on the transformation of BALB/3T3 cells, but to restrain the promotion by TPA.
Teratog Carcinog Mutagen 1990
PMID:Effects of quercetin, a plant flavonol, on the two-stage transformation in vitro. 198 35

In order to study the reliability of in vivo sister chromatid exchange (SCE) assays for predicting carcinogenicity, several known animal carcinogens were tested in a multicellular in vivo SCE assay and an in vivo/in vitro murine lymphocyte assay. The methylating agents 1,2-dimethylhydrazine.2 HCl (DMH), dimethylnitrosamine (DMN), methylnitrosourea (MNU), methyl methane-sulphonate (MMS), and methylazoxymethanol acetate (MAM) were tested for SCE induction in several murine tissues in vivo, including bone marrow, alveolar macrophages, regenerating and intact liver, and kidney from B6D2F1 mice. In all cell types, clear dose-responses were observed following exposure of mice to subcytotoxic fractions of the LD50 dose of DMH, MNU, or MMS. DMN (0.03-0.27 mmol/kg) produced small, although not dose-related, increases in SCE in all cell types. At the doses tested (0.06 and 0.08 mmol/kg), MAM did not induce elevated SCE in the various cell types. Following a series of multiple i.p. injections of low, non-toxic doses of DMH (0.15 mmol/kg, once a week, for 10 weeks), significant differences were observed in intact vs. regenerating liver and in single vs. multiple injections in regenerating liver. Following exposure of B6D2F1 mice to a single i.p. injection of 0.25 mmol/kg DMN, DMH, or MMS or 0.19 mmol/kg MNU, SCE responses were evaluated in Concanavalin A (Con A)- and LPS-stimulated blood and spleen lymphocytes. Considerable cytotoxicity was observed in blood lymphocytes. In Con A- and LPS-stimulated spleen lymphocytes, DMH-, and DMN- and MMS-induced SCE frequencies were approximately 1.5-2 x baseline levels and MNU-induced SCE were approximately three- to fourfold higher than baseline values in cultures initiated at 1 and 24 h postexposure. At 48 and 72 h after an i.p. injection of 0.131 mmol/kg MNU, SCE responses in lymphocytes were approximately 2 x baseline levels. At 24 h following one, two, or four injections (one/week) of 0.075 mmol/kg MNU dose-related increases in SCE were observed in spleen lymphocytes. These studies illustrate that carefully designed in vivo SCE assays may have the capacity to predict the tumorigenic potential of chemical agents.
Teratog Carcinog Mutagen 1989
PMID:Induction of sister chromatid exchange in multiple murine tissues in vivo by various methylating agents. 257 66

The mutagenic effects of sodium bisulfite on Salmonella typhimurium LT2 strains carrying the hisG46 allele were investigated. Treating the cells with 1 M sodium bisulfite in 0.2 M acetate buffer (pH 5.2) for various time intervals at 37 degrees C resulted in an increase in the yield of mutants above the spontaneous level. The fold enhancement of the mutant yield and the fold enhancement of the mutant frequency were greatest for the parent strain hisG46 with wild type DNA repair; the derived strains with reduced repair capacity responded to a lesser degree. While sodium bisulfite was mutagenic when tested in liquid suspension assays, strain hisG46 did not respond when the standard Ames plate incorporation assay was used. The greater mutagenic response in repair-proficient strains suggests that normal repair capacities may favor the mutagenic activity of sodium bisulfite. Transduction studies demonstrated that mutations of his+ were closely linked to the hisD gene, and probably were in the structural hisG gene itself.
Teratog Carcinog Mutagen 1985
PMID:The mutagenicity of sodium bisulfite on base-substitution strains of Salmonella typhimurium. 286 2

The influence of ethanol consumption on cleft palate induction by methylmercury, cortisone, and retinyl acetate was investigated in Swiss white mice. Consumption of 20% ethanol throughout gestation significantly increased the incidence of cleft palate compared to water-fed mice, when methylmercury was given on four consecutive days (days 9-12, 5 mg/kg of body weight). Ethanol also increased the incidence of cleft palate in mice given retinyl acetate (3,400 or 5,100 IU) on day 12, compared to retinol acetate-treated mice given water, but did not affect cleft palate induction by cortisone (2.5 mg/d, days 8-11). Ethanol significantly reduced fetal weight in the presence or absence of the three teratogens, but the results do not support a hypothesis that growth retardation is directly responsible for the potentiating action of ethanol. It may be that ethanol acts to increase cleft palate induction by some teratogens by retarding fetal developmental processes.
Teratog Carcinog Mutagen 1985
PMID:Potentiation of chemically induced cleft palate by ethanol ingestion during gestation in the mouse. 287 28

Male mice (C57BL/6J) at 2 weeks of age were divided into two groups and maintained on a vitamin A-deficient or vitamin A-(retinyl acetate) supplemented diet. After 8 weeks, the average liver vitamin A concentration of mice fed on vitamin A-deficient or -supplemented diet was 36 +/- 7 micrograms/g vs 287 +/- 22 micrograms/g, respectively. Uninduced liver S9 fractions were prepared from both groups of mice and used to activate (with cofactors) the precarcinogens aflatoxin B1 (AFB), cyclophosphamide (CPP), dimethylbenz(a)anthracene (DMBA), and benzo(a)pyrene (BP) in the Salmonella mutagenicity assay. S9 fraction prepared from both groups of mice failed to activate CPP to metabolites mutagenic in tester strains TA100 and TA1535 or to activate DMBA to metabolites mutagenic in TA100, but effectively activated AFB and BP to metabolites mutagenic in TA98. Comparison of activation activities of S9 prepared from liver of mice fed a high or low level of vitamin A was made with T98 treated with AFB or BP using three doses of S9 (50, 100, and 200 microliters/plate). S9 fractions from mice with a high liver vitamin A level were consistently less potent than S9 fractions from mice with a low liver vitamin A level in activating AFB to its mutagenic metabolites. This effect was not observed in BP-treated plates. Administration of AFB to groups of mice with a high liver vitamin A level induced significantly less SCE in bone marrow cells than did administration of AFB to mice with a low liver vitamin A level. This differential sensitivity was not observed when the two groups of mice were treated with either BP or CPP. The possible relationship between vitamin A levels in vivo and mutagenesis or carcinogenesis are discussed briefly.
Environ Mutagen 1986
PMID:Influence of mouse liver stored vitamin A on the induction of mutations (Ames tests) and SCE of bone marrow cells by aflatoxin B1, benzo(a)pyrene, or cyclophosphamide. 309 8

We have determined the skin tumor initiating activity in SENCAR mice of several 9- and 10-substituted mono- and dimethylbenz[a]anthracene derivatives. 9-fluoro-7-methylbenz[a]anthracene (9-F-7-MBA) was approximately as active as 7-MBA, whereas 10-F-7-MBA was considerably more active as a skin tumor initiator than the parent compound. Initiating doses of 200 and 400 nmol per mouse of 10-F-7-MBA yielded 14.17 +/- 0.16 and 22.47 +/- 1.64 papillomas per mouse after 18 weeks of promotion with 12-O-tetradecanoylphorbol-13-acetate, whereas comparable doses of 7-MBA yield 2.13 +/- 0.12 and 4.73 +/- 0.68 papillomas per mouse respectively. The effect of fluoro substituents at positions 9 and 10 of 12-MBA, a less potent tumor-initiator than 7-MBA, was also examined. 9-F-12-MBA was only slightly more active than 12-MBA, whereas 10-F-12-MBA was again considerably more active than the parent compound. Doses of 400 and 800 nmol per mouse of 10-F-12-MBA yielded 24.97 +/- 2.18 and 22.20 +/- 6.47 versus 1.13 +/- 0.80 and 3.00 +/- 0.17 papillomas per mouse respectively for comparable initiating doses of 12-MBA. The effect of introducing a trifluoromethyl (CF3) group at the 9 and 10 positions of 7,12-dimethylbenz[a]anthracene was also examined. A CF3 group at either of these positions essentially eliminated the tumor initiating activity of DMBA at the doses tested. These results when taken together with previous results from our laboratory suggest that electron donating substituents at positions 9 and 10 of the benz[a]anthracene nucleus either have no effect or enhance skin tumor initiating activity, whereas electron withdrawing groups at these positions dramatically reduce or abolish tumor initiating activity.
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PMID:Skin tumor initiating activities of the 9- and 10-fluoro derivatives of 7- or 12-methylbenz[a]anthracene and the 9- and 10-trifluoromethyl derivatives of 7,12-dimethylbenz[a]anthracene in SENCAR mice. 311 16

SRI used the L5178Y mouse lymphoma cell forward mutation assay to determine the mutagenic activity of 63 coded chemicals from 16 chemical classes. Replicate experiments were performed to assess the reproducibility of the assay within the laboratory. The evaluations (positive or negative) of the first two repeat experiments with the chemicals were the same for 116 (87%) of 134 tests. Evaluational differences between the first two experiments were fewer in the presence of induced S9 (6 tests) than in the absence of S9 (12 tests). The most commonly observed variability was the magnitude of positive mutagenic responses; this may be attributed to factors such as compound solubilities, S9 activation conditions, and differential recovery of mutant cells. Some consistency was observed in the responses of compounds of various chemical classes. Generally, antibiotics (ABO) and the azo dyes, azoxy and hydrazo compounds, diazoalkanes, nitriles and azides (AZO), were mutagenic with S9; alkyl, acyl, and aryl halides, halogenated ethers, and halohydrins (HAL) were more strongly mutagenic with than without S9; and monofunctional polycyclic aromatic hydrocarbons and fluorenones (PAH) were mutagenic only with S9. Amine-1-oxides (AMO), alkyl and aryl epoxides (EPO), and nitroalkanes, nitroaromatics, nitroquinolines, nitrofurans, and nitroimidazoles (NIT) were mutagenic with and without S9; amides, sulfonamides, aromatic amines, aliphatic amines, hydroxylamines, and benzidine and its derivatives (AMI) were mutagenic without S9; and methyl carbamate (the only monofunctional carbamate) and thioureas (CBM) induced a negative response under both conditions.
Environ Mol Mutagen 1988
PMID:Evaluation of the L5178Y mouse lymphoma cell mutagenesis assay: intralaboratory results for sixty-three coded chemicals tested at SRI International. 341 41


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