Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: DrugBank:APRD00249 (Mutagen)
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Chemical agents that possess the ability to alter tumorigenicity of carcinogens (administered at subthreshold dose) constitute a major health hazard. We have employed the Ames Salmonella assay to examine the effect of co-carcinogenic benzo[e]pyrene (B[e]P) on microsome-mediated chemical mutagenesis. B[e]P enhanced the mutagenic activity induced by 2-acetylaminofluorene (2-AAF) and benzo[a]pyrene (B[a]P) in strains TA1538 and TA98. Enhancement was also noted with N-hydroxy-2-AAF (the proximal metabolite of 2-AAF) but not with an ultimate carcinogenic form (N-acetoxy-2-AAF). These results suggest the use of this approach to detect chemical agents that possess the ability to alter the activity of mutagenic or carcinogenic chemicals.
Environ Mutagen 1979
PMID:Effect of the co-carcinogen benzo[e]pyrene on microsome-mediated chemical mutagenesis in Salmonella typhimurium. 39 7

Two photoproducts, derived from UV-irradiation of the amino acid L-tryptophan and with high Ah (TCDD) receptor binding affinity, were tested for genotoxic and antimutagenic effects. The two indolo[3,2-b]carbazole derivatives, with the molecular weights of 284 and 312, respectively, were tested in Saccharomyces cerevisiae strain D7 for mitotic gene conversion and reverse mutation and in strain RS112 for sister chromatid conversion and gene conversion. No significant (P > 0.05) genotoxic effects were found in strain D7, while strain RS112 showed a small but significant increase in the frequency of sister chromatid conversions. In Chinese hamster ovary (CHO) cells the two compounds induced a statistically significant but less than twofold increase in the frequency of sister chromatid exchanges (SCE). No mutations were detected when the compounds were tested in Salmonella typhimurium strains TA98 and TA100. However, both 284 and 312 acted as antimutagens on strain TA100 + S9 in the presence of benzo(a)pyrene. The decrease in mutagenicity by the most potent compound 284 was 20 revertants/nmol. This effect could be explained by an inhibitory effect on the cytochrome P450-dependent ethoxyresorufin O-deethylase (EROD) activity as seen in rat hepatocytes. The two compounds were also tested with hamster cells expressing rat cytochrome P-450IA1. The results support the conclusion that this cytochrome P-450 isozyme is inhibited by the tryptophan photoproducts. Similar results were also seen with two other high affinity Ah receptor ligands the quinazolinocarboline alkaloids rutaecarpine and dehydrorutaecarpine.
Environ Mol Mutagen 1992
PMID:Certain tryptophan photoproducts are inhibitors of cytochrome P450-dependent mutagenicity. 133 May 48

Mutagen-sensitive (mus) mutations in Drosophila melanogaster render developing flies hypersensitive to the lethal effects of DNA-damaging agents. In principle, multiply mutant mus strains might then serve as sensitive in vivo indicators of a wide range of mutagens and genotoxic carcinogens. As a first step to evaluate that potential we characterized interactions between mus mutations in eight double mutants containing combinations of the second chromosomal mutations mus201D1, mus205B1, mus208B1, mus210B1 and mus211B1. We found that (i) all double mutants are fully viable in the absence of mutagen exposure, (ii) mus205B1 is epistatic to any other mus mutation with respect to methyl methanesulfonate (MMS) sensitivity, and (iii) in double mutants carrying any combination of mus201D1, mus210B1 or mus211B1, MMS sensitivity is increased in a synergistic manner. Based on those results, and on mutagen cross-sensitivity data of single mutants generated in previous studies, we constructed two triple mutant mus strains for use as testers in a simple genotoxicity assay. That assay measures the survival of DNA repair-deficient mus homozygotes relative to their repair-proficient heterozygous siblings. Those two classes of fly are easily distinguished from one another by their phenotypic markers. In addition, the heterozygotes serve as a relatively mutagen-insensitive internal control in all test vials. One tester strain (mus208B1 mus210B1 mus211B2) identified 11 of 12 chemical carcinogens as genotoxic (benzo[a]pyrene, cyclophosphamide, 1,2,3,4-diepoxybutane, diethylnitrosamine, dimethylnitrosamine, ethyl methanesulfonate, formaldehyde, hexamethylphosphoramide, methyl methanesulfonate, methylnitrosourea and N-methyl-N'-nitro-N-nitrosoguanidine). Safrole and two noncarcinogens (benzo[e]pyrene and caprolactam) tested as nongenotoxic.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:A rapid somatic genotoxicity assay in Drosophila melanogaster using multiple mutant mutagen-sensitive (mus) strains. 147 14

Coumarin has been shown to be an effective inhibitor of carcinogenesis in rodents if given before and during the carcinogen treatment. We investigated the possibility that pretreatment with coumarin would inhibit the genotoxicity of benzo(a)pyrene (BP) in ICR mice as indicated by the bone marrow micronucleus test, a widely used in vivo test for genotoxicity. Our studies showed that pretreatment of male mice with doses of coumarin at 65 or 130 mg/kg/day for 1 week (with 1 day of no treatment at midweek) partially inhibited the genotoxicity of BP at a single intraperitoneal dose of 150 mg/kg. Time course experiments showed a decrease in induced micronuclei in the bone marrow at several time points after the BP treatment, thus indicating a true inhibition and not a lag in the induction of micronuclei. However, no inhibition in micronuclei formation was seen in female mice pretreated with the same doses of coumarin. Coumarin treatment alone did not induce micronuclei in either sex. Future studies are needed to analyze the mechanisms responsible for the difference noted between the sexes.
Environ Mol Mutagen 1992
PMID:Coumarin inhibits micronuclei formation induced by benzo(a)pyrene in male but not female ICR mice. 154 Dec 54

Comparison of the mutagenicity of nine isomeric benzo(a)pyrenyl [B(a)P] phenols conjugated with either sulfate or glucuronide was carried out using strain Salmonella typhimurium TA98. Of the nine conjugates tested, only B(a)P-1-sulfate was mutagenic. Accordingly, the mutagenicity of B(a)P-1-sulfate was compared with that of B(a)P and 1-hydroxybenzo(a)pyrene [B(a)P-1-OH] in the presence and absence of rat lung S9 and Aroclor-induced liver S9 with and without an NADPH-generating system. B(a)P-1-sulfate was slightly mutagenic, whereas B(a)P and the 1-hydroxy derivative were nonmutagenic when S9 fractions and NADPH were omitted. Addition of induced liver S9 with NADPH caused mutagenicity with B(a) -1-OH greater than B(a)P greater than B(a)P-1-sulfate. B(a)P-1-sulfate was the only mutagenic species when lung S9 was added. This mutagenicity did not require NADPH. Sodium sulfite, an inhibitor of arylsulfatase, decreased the mutagenicity of B(a)P-1-sulfate. These data suggest that a unique mutagenic species is generated from B(a)P-1-sulfate via arylsulfatase in rat lung.
Environ Mol Mutagen 1992
PMID:Mutagenicity of benzo(a)pyrenyl-1-sulfate in the Ames test. 157 48

Our recent syntheses of chryseno[4,5-bcd]thiophene together with its potential sulfone metabolite, chryseno[4,5-bcd]thiophene-4,4-dioxide, have made these compounds available for genotoxicity testing. Such toxicity testing is of interest as this thiophene is an isoster of the established carcinogen benzo[a]pyrene and is one of the thiaarenes which are potential environmental contaminants found in fossil fuels. Although the thiophene was less mutagenic than benzo[a]pyrene in Salmonella strains TA98 and TA100 after S9 activation, it exhibited in vivo chromosomal aberration activity equal to that of benzo[a]pyrene in the bone-marrow cells of mice. A reduced activity with Salmonella as well as in the bone-marrow cell assay for the sulfone does not support its role as the key active metabolic intermediate for the genotoxicity of the thiophene. Our molecular orbital calculations would be consistent with the concept of activation through a diol-epoxide mechanism and offers an explanation for the reduced genotoxicity of the sulfone via this mechanism. These genotoxicity studies support the concern that sulfur isosters of established carcinogenic polycyclic aromatic hydrocarbons could themselves be toxic.
Environ Mol Mutagen 1992
PMID:Genotoxicity of chryseno[4,5-bcd]thiophene and its sulfone derivative. 157 49

The SOS chromotest was applied for the detection of antimutagens. To raise SOS induction, the bacteria were treated with the mutagens, UV, 4-nitroquinoline N-oxide (4NQO), N-methyl-N'-nitro-N-nitroso-guanidine (MNNG), or benzo[a]pyrene (B[a]p). The inhibitory effects of L-ascorbic acid, glutathione, vanillin, 5-fluorouracil (5-FU), 5-chlorouracil (5-CU), cobaltous chloride, sodium selenite and sodium arsenite, which are known as antimutagens, were investigated with their addition either simultaneously or post treatment time. It became clear that the SOS chromotest was very useful for the detection of antimutagens.
Environ Mol Mutagen 1991
PMID:Evaluation of the SOS chromotest for the detection of antimutagens. 164 15

Rat lymphocytes are a potentially useful and convenient cell system for monitoring the genotoxic effects of chemicals in vivo, but little is known about the ability of these cells to metabolize promutagens to genotoxic species. In this study, Fischer 344 rat lymphocytes were treated in vitro with benzo[a]pyrene (BaP), 2-acetylaminofluorene (2-AAF), and several of their metabolites, and DNA damage was measured using nucleoid sedimentation analysis. Of the BaP derivatives, BaP 4,5-oxide and BaP 7,8-diol-9, 10-epoxide decreased lymphocyte nucleoid sedimentation, whereas BaP and BaP 7,8-dihydrodiol had little effect. Among the 2-AAF derivatives, N-acetoxy-2-AAF, N-hydroxy-2-AAF, and N-hydroxy-2-aminofluorene damaged rat lymphocyte nucleoids, whereas 2-AAF, 2-aminofluorene, and fluorene produced little detectable damage. The decrease in nucleoid sedimentation produced by N-hydroxy-2-AAF was not inhibited by paraoxon, salicylamide, or 2-aminofluorene, whereas paraoxon inhibited damage produced by N-acetoxy-2-AAF. In co-culture assays, rat lymphocytes increased the mutagenicity of N-hydroxy-2-AAF in Salmonella typhimurium strain TA98, but mediated little or no mutagenic response with BaP, BaP 7,8-dihydrodiol, and 2-AAF. Also, human lymphocytes, but not rat lymphocytes, mediated a positive mutagenic response with BaP 7,8-dihydrodiol in Chinese hamster ovary UV5 cells. Although rat lymphocytes may metabolize certain proximal genotoxic chemicals to DNA-damaging species (e.g., N-hydroxy-2-AAF), these data suggest that in vivo lymphocyte DNA damage is more likely to result from lymphocytes encountering reactive chemical derivatives produced by other cells. It is also clear that differences exist between the ability of human and rat lymphocytes to activate promutagens, and this may impact on the use of the rat model to predict the genotoxicity of chemicals in humans.
Teratog Carcinog Mutagen 1991
PMID:Analysis of rat lymphocyte activation of benzo[a]pyrene, 2-acetylaminofluorene, and several of their metabolites to mutagenic and DNA-damaging species in vitro. 168 75

A short term, in vivo mutagenesis assay has been developed utilizing a lacl target gene contained within a lambda ZAP shuttle vector which has been incorporated into transgenic mice. Following chemical exposure, the target gene was recovered from mouse genomic DNA by mixing the DNA with in vitro lambda phage packaging extract. Mutations within the lacl target were identified by infecting host E. coli with the packaged phage and plating on indicator plates containing Xgal. Phage plaques with mutations in the lacl appeared blue, while intact phage were colorless. The ratio of blue plaques to colorless plaques is a measure of the mutagenicity of the compound. This system was used to obtain significant induction (up to 74-fold) over background levels for a variety of compounds, including N-ethyl-N-nitrosourea, benzo(a)pyrene (BaP), cyclophosphamide, and methylnitrosourea. Sequence analysis of selected mutant clones derived from this system was accomplished through the use of partial filamentous phage origins which allow rapid transfer of the target gene from phage to plasmid. Sequence analysis of spontaneous mutants derived from the mice primarily found of base substitutions, differing markedly from the previous data for spontaneous mutations in lacl derived from E. coli, where the preponderance of mutations were found at a single site, a repeated tetramer sequence. Upon sequence analysis of BaP derived base substitutions, only transversions were obtained, consistent with the known mechanism of BaP mutagenesis. Use of the well-characterized lacl gene in transgenic mice should allow for extrapolation of the extensive pool of in vitro data to whole animals, as well as provide insight into the tissue specific effects of mutagenic compounds.
Environ Mol Mutagen 1991
PMID:Analysis of spontaneous and induced mutations in transgenic mice using a lambda ZAP/lacI shuttle vector. 183 79

The genotoxicity of the terpene beta-myrcene was evaluated in mammalian cells in vitro. Myrcene is the major constituent of oil of bay and hop which are used in the manufacture of alcoholic beverages. Myrcene is also present in lemon grass (Cymbopogon citratus), a plant widely used in Brazilian folk medicine. Recently, it was shown that myrcene is a very potent analgesic substance and might be an alternative to the already available analgesic drugs. Myrcene was tested up to 1,000 micrograms/ml (limit of solubility) in the presence and absence of S9-mix and did not induce chromosome aberrations and sister chromatid exchanges (SCEs) in human lymphocytes in vitro. Neither the mitotic index nor the proliferation index was influenced by the myrcene treatment. Myrcene did not cause increased mutation frequencies at the hprt-locus in V79-cells. Tests with and without S9-mix revealed negative results. There was no indication for induced cytotoxicity. However, myrcene reduced the SCE-inducing effect of cyclophosphamide in human lymphocytes in a dose dependent manner and also reduced the toxic and mutagenic effect of cyclophosphamide in V79-cells. Under the same test conditions, SCE induction by ethyl methanesulfonate (EMS) and benzo [a]pyrene (BP) was not significantly influenced by simultaneous myrcene treatment. The in vitro results show that myrcene is not mutagenic in mammalian cells, but has antimutagenic properties. The possibility that myrcene exerts its antimutagenic activity by inhibiting certain forms of the cytochrome P-450 isoenzymes required for activation of premutagens and precarcinogenes is discussed.
Environ Mol Mutagen 1991
PMID:Evaluation of the mutagenicity of beta-myrcene in mammalian cells in vitro. 186 66


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