Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: DrugBank:APRD00249 (Mutagen)
 5,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The alkylating anticancer drugs, mechlorethamine (HN2), chlorambucil, cyclophosphamide, carmustine and lomustine readily induced cytotoxicity in isolated rat hepatocytes. Hepatocyte glutathione (GSH) was depleted rapidly following addition of the drugs. Lipid peroxidation ensued following GSH depletion and before cytotoxicity occurred. Furthermore, cytotoxicity was delayed by the antioxidants butylated hydroxyanisole (BHA) and alpha-tocopherol, the ferric iron chelator desferoxamine or the radical trap 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) even when added 10 min later. HN2 was much less toxic to hepatocytes under nitrogen and caused much less lipid peroxidation than under aerobic conditions. Cytotoxicity induced by HN2 was also prevented by choline, suggesting that a choline carrier is responsible for HN2 uptake in the hepatocytes. Various sulfur compounds acted as antidotes for HN2 cytotoxicity. Thiosulfate was still effective when added 30 min after HN2. Depletion of GSH in the hepatocytes markedly increased their susceptibility to HN2. However, BHA, desferoxamine or TEMPO protected these hepatocytes from HN2. This suggests that antioxidants could prove useful in preventing the increased risk of hepatotoxicity if GSH-depleting agents are used to overcome tumor resistance to nitrogen mustards.
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PMID:Hepatocyte toxicity of mechlorethamine and other alkylating anticancer drugs. Role of lipid peroxidation. 159 84

Twenty-seven chemicals were tested for their mutagenic potential in the L5178Y tk+/tk- mouse lymphoma cell forward mutation assay using procedures based upon those described by McGregor et al. (McGregor DB, Martin R, Cattanach P, Edwards I, McBride D, Caspary WJ (1987): Environ Mol Mutagen 9:143-160). Cultures were exposed to the chemicals for 4 hr, then cultured for 2 days before plating in soft agar with or without trifluorothymidine (TFT), 3 micrograms/ml. The chemicals were tested at least twice. Statistically significant responses were obtained with acid orange 10, aniline, benzaldehyde, o-chloroaniline, chlorodibromomethane, cytembena, 1,2-dibromo-4-(1,2-dibromomethyl) cyclohexane, dieldrin, lithocholic acid, oxytetracycline, phenazopyridine HCl, 1-phenyl-3-methyl-5-pyrazolone, sodium diethyldithiocarbamate, solvent yellow 14, tetraethylthiuram disulfide (disulfiram), 2,4-toluene diisocyanate, and 2,6-toluene diisocyanate. Apart from phenazopyridine HCl, acid orange 10, and solvent yellow 14, rat liver S9 mix was not a requirement for the mutagenic activity of these compounds. Chemical not identified as mutagens were N-4-acetylaminofluorene, chlorpheniramine maleate, chloropropamide, 1,4-dioxane, endrin, ethylene glycol, iron dextran, methapyrilene, sodium(2-ethylhexyl)alcohol
Environ Mol Mutagen 1991
PMID:Responses of the L5178Y mouse Lymphoma cell forward mutation assay. V: 27 coded chemicals. 190 15

Epithelium from the neonatal mouse uterine cervix and uppermost part of vagina was cultured in vitro. The culture medium was supplemented with 17 beta-estradiol (E2; 10(-6)-10(-5) M) or diethylstilbestrol (DES; 10(-8)-10(-5) M) alone or in combination with different metabolic modifiers (alpha-naphthoflavone, beta-naphthoflavone, phenobarbital, metyrapone, indomethacin) with postulated activating or inhibitory effects on DES metabolizing enzymes (cytochrome P-448- and P-450-dependent microsomal monooxidases, prostaglandin cyclooxygenase). E2 at 10(-5) M and DES at 10(-6) and 10(-5) M concentrations increased the incidence of cells with a high number of sister chromatid exchanges (high-frequency chromatid exchange cells, HFCEC). Indomethacin partially depressed DES-induced HFCEC, whereas the incidence was increased by alpha-naphthoflavone, which may be a result of stimulation of the fetal type of P-448-dependent enzyme activity or of DES increasing the metabolic activation of alpha-naphthoflavone. Phenobarbital and beta-naphthoflavone did not affect the incidence of DES-induced HFCEC. Metyrapone alone induced the highest incidence of HFCEC observed in this study, and this effect was inactivated by phenobarbital and/or DES. The mechanisms behind these results are discussed. This study shows that E2 and DES have a genotoxic effect (sister chromatid exchanges) in vitro in epithelial cells from the same target organ as in which epithelial aberrations occur after in vivo estrogen treatment in the neonatal period. The difference in incidence of tetraploid cells between stroma and epithelium is stressed (less than 5% vs. 16-47% depending on experimental group).
Teratog Carcinog Mutagen 1989
PMID:Genotoxic effects of estrogens in epithelial cells from the neonatal mouse uterine cervix: modifications by metabolic modifiers. 256 25

The ciliated protozoan Paramecium was used to quantitate cytotoxic and genotoxic effects of nickel particles. The biological response of these eukaryotic cells to pure nickel powder and iron-nickel powder was assayed and compared to the effect of the inorganic carcinogen nickel subsulfide. Cytotoxicity was determined by the percent survival of treated cells. Genotoxicity was indicated by significant increases in the fraction of nonviable offspring (presumed index of lethal mutations) found after self-fertilization (autogamy) in parents from the nickel-treated versus neutral control groups. The cells were exposed to the dusts and the biological effects determined. Only the nickel subsulfide consistently showed a significant increase in offspring lethality.
Environ Mutagen 1986
PMID:Bioassay of environmental nickel dusts in a particle feeding ciliate. 373 99

Pretreatment with Metopirone (40 mg.) or SKF 525-A (2 mg./100 g. maternal body weight) protected aganist the embryotoxic and teratogenic actions of7-OHM-12-MBA) (2.5 mg/100 g. maternal body weight) in the Sprague-Dawley rat. At the doses administered SKF-525-A was a more efficient protector than Metopirone. The adrenocorticolytic actions of 7-OHM-12-MBA in the maternal adrenal glands were also prevented by these compounds and a close correlation existed between the degree of protection of the maternal adrenals and of the foetuses. It is suggested that the ultimate embryopathic substance is a metabolite of 7-OHM-12-MBA.
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PMID:Protection from the embryopathic effects of 7-hydroxymethyl-12-methylbenz(a)anthracene by 2-methyl-1,2-bis-(3-pyridyl)1-propanone(metopirone, Ciba) and beta-diethylaminoethyldiphenyl-n-propyl acetate (SKF 525-A). 547 2

Mutagen formation during frying of beef is inhibited by the heavy metal chelator ethylenediaminetetracetic acid (EDTA). The addition of 1% EDTA prior to cooking reduces the mutagenicity of the basic extracts to about 60% of control values. The addition of iron as ferrous chloride or ferric chloride at 10 ppm (approximately 50% of endogenous concentrations) doubles the mutagenic activity of beef extracts. Iron, which can be released by denaturation of heme protein, therefore, can modulate the formation of mutagens in beef during cooking.
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PMID:Formation of mutagens in cooked foods. VI. Modulation of mutagen formation by iron and ethylenediaminetetracetic acid (EDTA) in fried beef. 643 81

Several metals are known mutagens and carcinogens. These metals effectively displace acridine orange from DNA when measured by fluorescence polarization. Displacement of 50% of the acridine orange is obtained with less than 0.5 mM concentrations of lead, manganese, cobalt, zinc, cadmium, nickel, iron, copper, and cis-platinum. In contrast, greater than 80 mM concentrations of lithium, sodium, and potassium are required to displace an equivalent amount of acridine orange from calf thymus DNA. Although cis-platinum shows the best DNA reactivity in this assay, the interaction between this metal and DNA does not occur immediately, as it does for the other metals tested. These results indicate the acridine orange displacement assay provides a relative measure of the interaction of metals with DNA, and this DNA reactivity shows a positive correlation with mutagenic/carcinogenic potential.
Environ Mutagen 1981
PMID:Metal mutagens and carcinogens effectively displace acridine orange from DNA as measured by fluorescence polarization. 679 55

Quartz, the most common form of crystalline silica, was tested quantitatively for neoplastic transformation in the mouse embryo cell line, BALB/3T3/A31-1-1. Five quartz dust samples of respirable size [Min-U-Sil 5 (MQZ); hydrofluoric-acid-etched MQZ (HFMQZ); Chinese standard quartz (CSQZ); DQ12; and F600] all induced significant levels of neoplastic transformation, showing dose-dependent increases in the frequency of morphologically transformed foci at lower tested doses and a plateau level of response at higher doses. The plateau levels reached by the five tested samples did not differ substantially (maximum transformation frequencies per 10(5) cells ranging from 53.2 for MQZ to 28.3 for HFMQZ). F600 had minimal cytotoxicity but transforming activity comparable to the other samples. Cells from all tested transformed foci, when injected s.c. in nude mice, grew as sarcomas. Cytogenetic analysis showed that all tested silica-transformed cell lines had acquired one to five additional marker chromosomes, of types not seen in untreated control lines, indicative of induced chromosomal translocations and amplification. Increased expression of one or more of five genes (p53, myc, H-ras, K-ras, and abl) was observed in several quartz-transformed cell lines. No transforming activity was found for hematite and anatase (both nontoxic), and for rutile (more toxic than MQZ). Combined exposure (1:1 w/w per unit culture area) of each of these dusts with MQZ showed that hematite and anatase inhibited MQZ toxicity as well as transformation, whereas rutile markedly enhanced MQZ toxicity but not MQZ-induced transformation.
Teratog Carcinog Mutagen
PMID:Neoplastic transformation by quartz in the BALB/3T3/A31-1-1 cell line and the effects of associated minerals. 873 83

Glutathione is activated to a mutagen by gamma-glutamyl transpeptidase. Other thiols, such as cysteine, penicillamine, cysteine ethylester, and cysteinylglycine, are direct mutagens in the Ames Salmonella mutagenicity test. Thiol mutagenesis is oxidative in nature and involves H2O2 and possibly hydroxyl radicals. Transition metals are crucial for thiol autoxidation. The role of copper and ceruloplasmin (CP) in thiol-dependent mutagenesis was studied in Salmonella typhimurium strain TA102. Cu and CP at low concentrations enhanced thiol-dependent mutagenesis in the presence, but not in the absence, of added Fe. The degree of enhancement depended on the type of thiol. At high Cu or CP concentrations, thiol mutagenesis was inhibited. Cu also decreased the mutagenicity of H2O2. Cu- and CP-enhanced mutagenesis were inhibited by radical scavengers, catalase, and peroxidase but not by superoxide dismutase. The effects of Cu and CP on thiol-dependent mutagenesis were similar to their effects on thiol-driven lipid peroxidation. The results indicate that the role of Cu and CP in the enhancement of thiol mutagenesis is the facilitation of the transfer of electrons from a thiol to iron, rather than in catalysis of the Fenton reaction.
Environ Mol Mutagen 1997
PMID:Role of copper and ceruloplasmin in oxidative mutagenesis induced by the glutathione-gamma-glutamyl transpeptidase system and by other thiols. 902 Mar 9

Oxidative damage (lipid peroxidation, LPO) induced in a completely defined system containing glutathione (GSH), purified gamma-glutamyl transpeptidase (GGT), and EDTA- and ADP-chelated ferric iron was enhanced by catalytic amounts of cupric ions and by ceruloplasmin (CP). The enhancement depended on GSH concentration, GGT activity, the presence of iron, and the chelation of copper by o-phenanthroline. High concentrations of CP inhibited LPO. Cu- and CP-enhanced, GSH-GGT-driven LPO was inhibited by the chain-breaking radical scavengers butylated hydroxyanisol, alpha-tocopherol, and Trolox C (a synthetic analog of alpha-tocopherol) but not by the hydroxyl scavenger mannitol. Ascorbic acid increased LPO in the presence of Cu or CP. Cu-enhanced LPO was partially sensitive to superoxide dismutase but not to catalase or horseradish peroxidase. The results indicate that Cu and CP enhance thiol-driven LPO and promote thiol-dependent mutagenesis by a very similar, if not the same, mechanism and are in agreement with the idea that this enhancement is due to redox reactions of chelated Cu and Fe, rather than to the reactivity of Cu in the Fenton reaction.
Environ Mol Mutagen 1997
PMID:Promotion of glutathione-gamma-glutamyl transpeptidase-dependent lipid peroxidation by copper and ceruloplasmin: the requirement for iron and the effects of antioxidants and antioxidant enzymes. 902 Mar 10


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