Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: DrugBank:APRD00249 (Mutagen)
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Rats treated with di(2-chloroethyl)methylamine (HN2), N-methyl-N-nitrosourea (MNUA) and N-ethyl-N-nitrosourea (ENUA) excrete significantly larger amounts of deoxycytidine (dC) and thymidine in their urine 0-24 h after treatment. Ethyl methanesulphonate (EMS) and dimethylnitrosamine (DMN) gave negative results in this respect but all five alkylating agents increased the excretion of 1-methyl-nicotinamide (1-meNmd). In addition, a larger quantity of 7-methylguanine (7MG) and uric acid was excreted after DMN treatment. 1,4-Dimethanesulphonoxybutane (myleran), 2,2-dichlorovinyl dimethyl phosphate (dichlorvos), 5-fluorouracil (5FU), cytosine arabinoside (araC), 2-acetylaminofluorene (AAF) and 7-bromomethylbenz-[a]anthracene (7-BrMBA) gave negative results.
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PMID:Increased urinary excretion of nucleic acid and nicotinamide derivatives by rats after treatment with alkylating agents. 12 32

7-Methylbenz(a)anthracene (7-MBA) and its 5,6-oxide and trans-5,6- and trans-8,9-dihydrodiol were tested for carcinogenic activity in a system in which mouse lung tissue was incubated in the presence of a test compound for 1 h and then implanted into isologous mice. All four compounds gave small yields of adenomas and in addition the 5,6-oxide gave two carcinomas.
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PMID:The activity of 7-methylbenz(a)anthracene metabolites in an in vitro-in vivo carcinogenicity test using mouse lung tissue. 40 82

Induction of skin tumors by 7,12-dimethylbenz(a)anthracene (DMBA) in the presence of its metabolites-7-hydroxymethyl-12-methylbenz(a)anthracene (7-OHM-12-MBA) and 7,12-dihydroxymethylbenz(a)anthracene (7,12-diOHMBA) has been studied in mice. The skin of mice was treated repeatedly with benzene or acetone solutions of DMBA (22 mug in two droplets) or with the same amount of DMBA solution together with one of the above mentioned metabolites (the molecular ratio 1 : 1 or 1 : 0.5). Neither of the metabolites affected the carcinogenic activity of DMBA under the given conditions. 7,8-benzoflavone, an inhibitior of the DMBA metabolism, strongly suppressed DMBA tumorigenesis under the same experimental conditions. Whereas the effect of benz(a)-anthracene, an inducer of aryl hydrocarbon hydroxylase activity, was less pronounced.
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PMID:[Effect of 7,12-dimethylbenz(alpha)anthracene metabolites on its capacity to induce skin tumors in mice]. 81 Sep 68

The crystal structure of the moderately active carcinogen 12-methylbenz[alpha]anthracene (12-MBA) has been determined by application of direct methods to X-ray single-crystal diffraction data. Least-squares refinement to a residual R = 0.09 over 929 independent reflections enabled carbon positions to be established with apparent e.s.d.s. of atomic coordinates about 0.008 A. Deviation from planarity is exemplified by the 15.5 degrees inclination of the benz ring (A) to the anthracene nucleus and by the 0.89 A distance of the methyl carbon out of the best plane through the whole benzanthracene nucleus. Comparison with the structure of the highly carcinogenic 7,12-dimethylbenz[alpha]anthracene (7,12-DMBA), and with the recently solved structures of the weak carcinogen 1-MBA and the extremely weak carcinogen 1,12-DMBA, shows a close similarity in the anthracene parts; in 1-MBA, and 1,12-DMBA, the phenanthrenic K-region bond is close to 1.34 A and the M-region bond about 1.38 A. In 12-MBA, overcrowding in the 'bay' region causes the central anthracene ring C and the benz ring A each to be bent about 10 degrees in opposite directions from the phenanthrenic B ring, much as in 1-MBA and 7,12-DMBA, but less than in 1,12-DMBA; the 12-methyl carbon lies about the same distance (0.55 A) above the anthracene plane in 12-MBA as in 1,12-MBA and 7,12-DMBA.
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PMID:Shapes of carcinogenic benz[alpha]anthracenes: an x-ray crystal structure analysis of 12-methylbenz[alpha]anthracene. 101 36

The influence of beta-carotene on the formation of DNA-adducts induced by 7,12-dimethylbenz(a)anthracene (DMBA) and 7-hydroxymethyl-12-methylbenz(a)anthracene (7-OHM-12-MBA) during transformation of mouse mammary cells in organ culture was analysed. Treatment with beta-carotene (10(-8)-10(-5) mol/l) caused inhibition (48.8-94.4%) of an adduct (VI), which was detectable in DNA samples from DMBA-treated mammary glands. Out of six adducts, derived from further analysis of DNA samples from 7-OHM-12-MBA-treated glands, adduct f eluted in the same fraction as adduct (VI), indicating these adducts were analogous. Likewise, adduct f was also inhibited by beta-carotene. Boronate chromatographic analysis revealed this particular adduct was a syn-dihydrodiol epoxide product. Adduct inhibition was detectable both at the start and after DMBA treatment. alpha-Tocopherol and canthaxanthin were ineffective in inhibiting adducts. It is reasonable to conclude that beta-carotene-mediated modification of adducts is associated with the inhibition of a syn-adduct, which is derived from further metabolism of a 7-OHM-12-MBA intermediate.
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PMID:beta-Carotene-mediated inhibition of a DNA adduct induced by 7,12-dimethylbenz(a)anthracene and 7-hydroxymethyl-12-methylbenz(a)anthracene in mouse mammary gland in vitro. 162 82

Detection of micronuclei (MN) in skin cells from HRA/Skh hairless mice treated with chemical or physical agents may prove informative in qualitative and quantitative studies of skin carcinogenesis. MN induction and cell survival were estimated in cytokinesis-blocked keratinocytes, cultured for 4 days in vitro, after a single topical dose of various organic compounds. Treatment with 2.56 micrograms (10 nmol) 7,12-dimethylbenz[a] anthracene (DMBA) resulted in maximal MN induction in cells removed from skin 12-24 hr after topical administration (79-88 MN/1,000 cells compared with 10-16 MN/1,000 cells in acetone-treated controls). Even in cells removed only 1 hr after DMBA treatment, a significant increase in MN was evident. However, to allow sufficient time for metabolic activation, a sampling time for of 24 hr was adopted for all test substances. Dose-dependent increases in MN were observed with DMBA, benzo[a]pyrene, chrysene, and urethane. Increased numbers of micronucleated cells were detected at the lowest doses administered in the present study (0.128, 0.5, 50, and 50 micrograms, respectively). Although reduced cell recovery occurred following exposure of mice to acetone, pyrene, and other chemicals, there was no evidence that cytotoxicity contributed to MN scored in keratinocytes. Moreover, the probable noncarcinogen, pyrene, failed to induce MN at doses from 2.5 micrograms to 2.5 mg/mouse. These results show that it is possible to assess chemical exposure in skin by measuring cell survival and skin genotoxicity by measuring MN induction in cultured keratinocytes. The available data suggest that MN induction may be a useful indicator of the carcinogenic potential of chemicals applied to the skin.
Environ Mol Mutagen 1991
PMID:Micronuclei in mouse skin cells following in vivo exposure to benzo[a]pyrene, 7,12-dimethylbenz[a]anthracene, chrysene, pyrene and urethane. 190 14

Primary cultures of mouse epidermal keratinocytes from SENCAR mice were treated with 7,12-dimethylbenz(a)anthracene (DMBA), benzo(a)pyrene [B(a)P], (+/-)7 beta-8 alpha-dihydroxy-9 alpha, 10 alpha-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene [(+/-)anti-BPDE], and (+/-)7 beta, 8 alpha-dihydroxy-9 beta, 10 beta-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene [(+/-)syn-BPDE] to examine the relationship between DNA adduct formation and the induction of unscheduled DNA synthesis (UDS). DNA adducts were measured as pmol hydrocarbon bound per mg of DNA, and UDS was quantitated autoradiographically as net grains per nucleus. A good correlation was observed between the levels of UDS detected and the amount of DNA adducts present in the cell population when comparing similar compounds within the linear dose-response range of 0.005 micrograms/ml-0.25 micrograms/ml. A higher rate of UDS for a given level of DNA adducts was interpreted as an increased efficiency of DNA repair. In some cases, an increase in the efficiency of DNA excision repair correlated with lower tumor-initiating activity. For this family of PAH, the concentration below which UDS could no longer be detected was approximately 0.01 microgram/ml. However, DNA adducts were measurable at concentrations of 0.01 and 0.005 micrograms/ml. The limits of detection of the current UDS assay in the SENCAR MEK culture system occurred at hydrocarbon adduct levels of approximately 10 pmol/mg DNA, or approximately 1 adduct per 3 x 10(5) bases. Additionally, the UDS assay was unable to detect DNA repair induced by the weakly carcinogenic PAHs, dibenz(aj)anthracene and 7-methyl-dibenz(aj)anthracene. The UDS assay did detect DNA repair by the more strongly carcinogenic PAH, 6-methylcholanthrene. These results suggest that the present UDS assay with MEKs is a useful assay for the rapid screening of potential genotoxic agents. However, the limits of sensitivity are such that the current assay may be unable to detect a low level of DNA damage induced by some weakly genotoxic (carcinogenic) agents. In addition, while the limits of sensitivity determined in these experiments apply to the polycyclic aromatic hydrocarbon class, other classes of genotoxic compounds such as alkylating agents or crosslinking agents may exhibit different thresholds of detection.
Environ Mol Mutagen 1991
PMID:Relationship between DNA adduct formation and unscheduled DNA synthesis (UDS) in cultured mouse epidermal keratinocytes. 191 14

1,2,3,4-Tetrahydro-7,12-dimethylbenz(a)anthracene (TH-DMBA), its six possible fluorosubstituted regioisomers, and the C-7 exo methylene tautomer of the 11F derivative have been investigated for their cytotoxicity and for their ability to induce anchorage-independent growth and to form adducts in human neonatal foreskin fibroblasts. All compounds tested exhibited a low level of cytotoxicity, determined as percent cloning efficiency, up to a final concentration of 30 micrograms/ml. Except for 5F-TH-DMBA and the C-7 exo methylene tautomer, all compounds induced anchorage-independent growth of neonatal foreskin fibroblasts in soft agar at all concentrations tested (1, 3, 10 and 30 micrograms/ml). The C-7 exo methylene tautomer induced anchorage-independent growth only at a concentration of 10 micrograms/ml. Among the compounds tested the 6F derivative was the most effective compound at 1 microgram/ml. The D-ring fluoro isomers induced anchorage-independent growth at a frequency comparable to TH-DMBA itself, with the 11F derivative being the least effective of the four D-ring regioisomers. All compounds except 5F-TH-DMBA formed detectable adducts with cellular DNA as determined by 32P postlabeling procedures, when the cells were treated at 1 microgram/ml. Two adducts were detected in cells treated with TH-DMBA and four adducts were detected in DNA obtained from cells treated with 6F-TH-DMBA. The level of bonding for the D-ring fluoro isomers was quantitatively less and sometimes qualitatively different than that for TH-DMBA. For the D-ring compounds, the ability to induce anchorage-independent growth frequency correlated with the total quantity of adduct formed. The C-7 exo methylene tautomer formed a single adduct and the level of bonding was less than one adduct per 10(9) nucleotides. Analysis of these results led to the proposal that the planar anthracene ring structure (rings B, C, and D) of TH-DMBA and possibly oxidative metabolism at benzylic carbon 4 of the A-ring are important to DNA bonding and initiation of induction of anchorage-independent growth.
Teratog Carcinog Mutagen 1990
PMID:Cytotoxicity, anchorage-independent growth, and DNA adduct formation in human neonatal fibroblasts by 1,2,3,4-tetrahydro-7,12-dimethylbenz(a)-anthracene (TH-DMBA), its six aryl fluoro regioisomers, and an exo methylene tautomer. 197 29

The adrenal cortex contains high amounts of detoxifying enzymes, as well as generators and protectors of reactive oxygen species. The high content of cytochrome P-450 enzymes in the adrenal cortex together with its remarkable tendency to accumulate hydrophobic substances probably contributes to the extraordinary vulnerability of the gland to a number of xenobiotics. The best studied adrenocorticolytic compounds are the potent carcinogen 7,12-dimethylbenz(a)anthracene (DMBA) and its liver metabolite 7-hydroxymethyl-12-methylbenz(a)anthracene (7-OHM-12-MBA). Adrenocorticolysis generated by these agents in vivo as well as in vitro demonstrates high regioselective requirements and is strongly influenced by the presence of ACTH, steroids, cytochrome P-450 inhibitors and antioxidants. Furthermore, 7-OHM-12-MBA has been demonstrated to uniquely generate selective and massive oxidation of mitochondrial glutathione in cultured rat adrenal cells. The DMBA-induced adrenocorticolysis is thoroughly discussed in this review with particular emphasis on the metabolism of DMBA and the influence of various effectors. A working hypothesis involving a possible peroxidative mechanism is also presented.
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PMID:Metabolism and toxicity of xenobiotics in the adrenal cortex, with particular reference to 7,12-dimethylbenz(a)anthracene. 212 60

1. 7,12-Dimethylbenz(a)anthracene (DMBA) and 7-hydroxymethyl-12-methylbenz(a)anthracene (7-OHM-12-MBA), but not benzo(a)pyrene (BP), selectively produce necrosis in the two inner zones of the rat adrenal cortex and are toxic to cultured rat adrenocortical cells. 2. The toxicity induced by 7-OHM-12-MBA in the adrenocortical cells was partially prevented by the inhibitor of the cyclooxygenase activity of prostaglandin H synthetase, indomethacin. In contrast, indomethacin did not influence the effect of BP and DMBA on these cells. 3. Two other effectors of the prostaglandin metabolism, 5,8,11,14-eicosatetraynoic acid (ETYA) and nordihydroguaiaretic acid (NDGA), as well as the anti-inflammatory steroids cortisol and dexamethasone, partially protected against, whereas arachidonic acid and bradykinin exacerbated, the cytotoxicity induced by 7-OHM-12-MBA. 4. These results indicate that prostaglandin metabolism may be involved in the necrotic mechanism of 7-OHM-12-MBA in rat adrenal cortex.
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PMID:Influence of effectors of prostaglandin metabolism on the toxicity induced by 7-hydroxymethyl-12-methylbenz(a)anthracene in cultured rat adrenal cells. 212 91


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