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Biomedical subjects

A Dipple

Publications and source records attributed to A Dipple.

At least 91 records · Page 5Linked to original sources
PubMed1983

Effects of butylated hydroxyanisole and butylated hydroxytoluene on 7,12-dimethylbenz[a]anthracene-DNA adduct formation in mouse embryo cell cultures.

Neither butylated hydroxyanisole (BHA) nor butylated hydroxytoluene (BHT) significantly reduced overall 7,12-dimethylbenz[a]anthracene (DMBA)--DNA adduct formation in mouse embryo cell cultures. However, analysis of DMBA--DNA adducts by Servacel DHB chromatography and high-pressure liquid chromatography showed that treatment of cells with BHA, but not with BHT, resulted in a decreased contribution from the syn bay region dihydrodiol epoxide to overall binding.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1983

Chromatographic and fluorescence spectroscopic studies of individual 7,12-dimethylbenz[a]anthracene--deoxyribonucleoside adducts.

Compared with standard Sephadex LH-20 column chromatography, a newly developed high pressure liquid chromatographic separation of hydrocarbon deoxyribonucleoside adducts derived from the DNA of mouse embryo cell cultures exposed to 7,12-dimethylbenz[a]anthracene (DMBA) provides markedly superior resolution. Once resolved, the fluorescence spectroscopic properties of the three major DMBA--DNA adducts indicate that the fluorescence exhibited by adducts derived from a bay region syn dihydrodiol epoxide of DMBA differs subtly from that exhibited by adducts derived from the isomeric anti dihydrodiol epoxide.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1983

Products of binding of 7,12-dimethylbenz(a)anthracene to DNA in mouse skin.

7,12-Dimethylbenz(a)anthracene (DMBA):deoxyribonucleoside-adducts, from enzymatic hydrolysis of DNA from mouse skin exposed to [3H]DMBA in vivo, were analyzed by reverse-phase high-pressure liquid chromatography. Double-labeling studies showed that the adducts were qualitatively identical to those formed in mouse embryo cell cultures. These have been tentatively identified as bay-region anti-dihydrodiol epoxide: deoxyguanosine- and :deoxyadenosine adducts and a bay-region syn-dihydrodiol epoxide:deoxyadenosine-adduct (where the terms syn and anti define dihydrodiol-epoxides wherein the benzylic hydroxyl group and epoxide oxygen are cis or trans to one another, respectively). The relative amounts of individual adducts did not vary substantially with time or with the sex of the mice. However, the syn-dihydrodiol-epoxide:deoxyadenosine-adduct did increase with dose and constituted as much as 40% of the total DNA binding at high doses of DMBA. This is in contrast to the much lower (2 to 3%) levels of binding to deoxyadenosine residues in mouse skin reported for the less potent tumor initiator benzo(a)pyrene. The greater reactivity of DMBA with deoxyadenosine residues in mouse skin may play a role in determining its greater tumor initiating potential.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1983

Formation, metabolism, and mechanism of action of polycyclic aromatic hydrocarbons.

Polycyclic aromatic hydrocarbons are generated through inefficient combustion and, while initially released largely into the atmosphere, they are subsequently deposited in soil and water. They contaminate marine sources of food as well as vegetables and plants and can be generated during the smoking or broiling of fish and meat. The metabolic fate of hydrocarbons in mammalian systems has been extensively studied and, while many hydrocarbons are noncarcinogenic and efficiently detoxified, small fractions of some hydrocarbons are converted to electrophilic metabolites which are not effectively further metabolized and which are probably responsible for the carcinogenic properties of these hydrocarbons. These electrophilic metabolites are probably the bay-region dihydrodiol-epoxides, but at present the tumorigenic properties of the bay-region dihydrodiol-epoxides that have been tested are not as great as might be expected.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1983

Involvement of both syn- and anti-dihydrodiol-epoxides in the binding of 7, 12-dimethylbenz(a)anthracene to DNA in mouse embryo cell cultures.

7,12-Dimethylbenz(a)anthracene (DMBA):deoxyribonucleoside adducts, from enzymic hydrolyses of DNA from mouse embryo cells exposed in culture to [3H]DMBA, can be separated into two fractions on the basis of whether or not they bind to the phenyl boronic acid residues of Servacel DHB. This suggests that these two fractions of adducts are derived from anti and syn bay-region dihydrodiol-epoxides, respectively. The fluorescence spectra and interactions of the major components of these two fractions with borate ions substantiate this interpretation. These findings indicate that both syn- and anti-dihydrodiol-epoxides make a substantial contribution to DMBA binding to DNA in mouse embryo cells. For a given mouse embryo cell preparation, the relative contributions of each of these dihydrodiol-epoxides to DNA binding did not vary substantially with DMBA dose, with incubation time with DMBA, or in growing versus confluent cultures, although there were differences between one cell preparation and another.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1983

Evidence that binding of 7,12-dimethylbenz(a)anthracene to DNA in mouse embryo cell cultures results in extensive substitution of both adenine and guanine residues.

Primary mouse embryo cell cultures were grown in the presence of [14C]guanine, labeling primarily deoxyguanosine residues in the cellular DNA, or in the presence of [14C]adenine, labeling both deoxyguanosine and deoxyadenosine residues in the cellular DNA. These cultures were subsequently exposed to 7,12-[3H]dimethylbenz(a)anthracene for 24 hr. The DNA was isolated and hydrolyzed to deoxyribonucleosides, and the 7,12-dimethylbenz(a)anthracene:deoxyribonucleoside adducts were separated chromatographically allowing the three major adducts found to be identified as bay-region anti-dihydrodiol-epoxide:deoxyguanosine and :deoxyadenosine adducts and a bay-region syn-dihydrodiol-epoxide:deoxyadenosine adduct. Therefore, in contrast to what is known for benzo(a)pyrene, substantial amounts of deoxyadenosine adducts are formed with the more potent carcinogen, 7,12-dimethylbenz(a)anthracene.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1982

X-ray crystallographic proof of electrophilic attack at the pyrimidine/imidazole ring junction in guanosine.

The crystal structure of a novel nucleoside isolated from guanosine/p-methylbenzyl chloride reactions demonstrates linkage between the methylene carbon of the benzyl moiety and carbon-5 of guanosine, and loss of the carbonyl function at carbon-6 of guanosine, to yield 4-(p-methylbenzyl)-5-guanidino-1-beta-D-ribofurasylimidazole. These findings suggest that carbon-5 of guanine in DNA is a potential site of reaction for electrophilic ultimate carcinogens.

Carcinogens↗
PubMed1981

Comparative carcinogenicity of alkylating agents: comparisons of a series of alkyl and aralkyl bromides of differing chemical reactivities as inducers of sarcoma at the site of a single injection in the rat.

A series of alkylating and aralkylating bromides was used in a comparative study of chemical reactivity (using 4-(p-nitrobenzyl) pyridine as standard nucleophile), and carcinogenic activity (using single injections by the subcutaneous route in 6-week old female CB-hooded rats). Benzyl, ethyl, isopropyl, and trityl bromides were inactive as carcinogens at doses up to 0.83, 12.5, 8.3 and 0.25 mmol/kg, respectively. 7-Bromomethylbenz[a]anthracene and 7-bromomethyl-12-methylbenz[a]anthracene gave high yields of sarcomas at the injection site (in the right flank); at the highest doses used, 35% yield of tumors was obtained using 0.25 mmol/kg 7-bromomethylbenz[a]anthracene, and 75% yield with 0.056 mmol/kg of the 12-methyl homologue. The order of chemical reactivity was trityl greater than 7-bromomethyl-12-methylbenz[a]anthracenyl greater than 7-bromomethyl-benz[a]anthracenyl greater than benzyl greater than ethyl greater than isopropyl. The relationship suggested between carcinogenicity and reactivity is that the highest reactivity permitted little in vivo penetration to essential cellular receptor sites because of immediate solvolysis, whereas the lower reactivities did not ensure sufficient alkylation of such receptors. The bromomethylbenz[a]anthracenes (of intermediate chemical reactivity) are known to react with DNA in vivo, but so far no differences in reactivity between them can account for their quantitatively different carcinogenic potencies.

Alkylating Agents↗
PubMed1981

Crystal structure of a carcinogen:nucleoside adduct.

The product of reaction between the carcinogen, 7-bromomethyl-12-methylbenz[a]anthracene, and 2'-deoxyadenosine, i.e., N6-(12-methylbenz[a]anthracenyl-7-methyl)deoxyadenosine, has been prepared and characterized, and its structure has been determined by X-ray crystallographic techniques. The major structural features are: (a) the adenine and polycyclic aromatic hydrocarbon residues lie nearly perpendicular to one another; (b) the conformation about the glycosidic bond is syn, rather than anti, and an internal hydrogen bond between the deoxyribose 5'-hydroxyl group and N(3) of the adenine residue is present; and (c) the more planar anthracene portion of the hydrocarbon is stacked between adenine residues of other molecules throughout the crystal.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1980

Evaluation of metabolic activation of 7,12-dimethylbenz(a)anthracene in vitro by aroclor 1254-induced rat liver S-9 fraction.

Short-term assays for detection of chemical carcinogens frequently rely on an Aroclor 1254-induced rat liver S-9 fraction for metabolic activation of test compounds. The ability of this in vitro system to reproduce the activation occurring in target tissue was investigated by examining the DNA adducts produced when the polycyclic aromatic hydrocarbon carcinogen, 7,12-dimethylbenz(a)anthracene (DMBA), was incubated with the S-9 fraction and calf thymus DNA. Analyses by Sephadex LH-20 column chromatography of hydrocarbon-deoxyribonucleoside adducts obtained after enzymic digestion of the [3H]DMBA-modified DNA revealed that the products of binding of DMBA to DNA in the presence of the S-9 fraction vary with the relative concentration of DMBA to S-9 fraction. Further analyses of these adducts by high-pressure liquid chromatography in the presence of the diol-epoxide-DNA adduct (isolated from mouse embryo cells exposed to [14C]DMBA) and chemically synthesized ultraviolet-absorbing markers of DMBA 5,6-oxide-deoxyribonucleoside adducts showed that, at high DMBA-S-9 ratios, DMBA 5,6-oxide-deoxyriboiucleoside adducts were prominent among the products while, at low DMBA-S-9 ratios, the products included the diol-epoxide-DNA adduct found in target tissue. However, this adduct was always accompanied by other adducts not found in intact cellular systems. Inclusion of a metabolic inhibitor (1,1,1-trichloropropylene oxide) in the Salmonella mutagenicity assay demonstrated that high levels of revertants can be obtained from rat liver S-9 fraction-activated DMBA under conditions which should prohibit formation of the diol-epoxide. These results suggest that Aroclor 1254-induced rat liver S-9 fraction does not exactly reproduce the metabolic activation of this particular carcinogen in vivo and therefore should not be assumed to do this for other carcinogens.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1979

Distribution of DNA damage in chromatin and its relation to repair in human cells treated with 7-bromomethylbenz(a) anthracene.

We have examined the relationship between the distribution of DNA damage and repair in chromatin from confluent human fibroblasts treated with the carcinogen 7-bromomethylbenz (a) anthracene. Analysis of staphylococcal nuclease (SN)4 digestion kinetics and gel electrophoresis revealed that more total damage occurs in nucleosome core DNA (approximately 80-85% of chromatin DNA) than in SN sensitive DNA (APPROXIMATELY15-20%). Furthermore, over a 24 hr period, damage is removed at about the same rate from these two regions. In contrast, virtually all of the nucleotides incorporated during repair synthesis are initially SN sensitive even when measured at 12 hr after damage. With time many repair-incorporated nucleotides become SN resistant and coelectrophorese with nucleosome core DNA. To explain these data we propose a model whereby excision repair occurs in both linker and core DNA; however, in core DNA the repair process induces conformational changes resulting in temporarily increased SN sensitivity; subsequently, rearrangement occurs and results in the re-establishment of native or near-native nucleosome conformation and SN resistance.

Benz(a)Anthracenes↗
PubMed1979

Fluorescence of hydrocarbon-deoxyribonucleoside adducts.

In comparison with the fluorescence emission spectra of 7-methylbenz[a]-anthracene-nucleoside adducts, the fluorescence emission spectra of hydrocarbon-deoxyribonucleoside adducts containing a methyl substituent in the "bay region" lack spectral resolution at room temperature and appear at substantially longer wavelength. This spectral resolution is improved when spectra are measured at 77 K and an irreversible spectral shift to shorter wavelength, accompanied by improved resolution, results from mild acid hydrolysis. These spectral properties peculiar to the "bay region-substituted" adducts presumably result from an intramolecular interaction between the hydrocarbon fluorophore and the attached nucleoside brought about, in the examples studied here, by the presence of the 12-methyl group in 7,12-dimethylbenz[awanthracene (DMBA) and in 7-hydroxymethyl-12-methylbenz[a]anthracene. This interaction suggests that the site of nucleoside attachment is in close proximity to the 12-methyl group and that binding occurs, therefore, through the intermediacy of a 3,4-diol-1,2-oxide, i.e. a "bay region" diol-epoxide in each case.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1979

Excision of DNA damage arising from chemicals of different carcinogenic potencies.

Primary cultures of mouse embryo cells are more efficient in excising DNA-carcinogen adducts resulting from exposure to either 7-bromomethylbenz-[alpha]anthracene or the more carcinogen 7-bromomethyl-12-methylbenz[alpha]anthracene than are mouse L 929 cell suspension cultures. However, within each of these systems, the excisabilities of the adducts formed by either bromo-compound are similar, so differences in carcinogenic potency of the compounds cannot be attributed to differences in the excisability of their DNA-adducts.

9,10-Dimethyl-1,2-benzanthracene↗