ABSTRACT
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.
Subject(s)
9,10-Dimethyl-1,2-benzanthracene , Benz(a)Anthracenes , DNA/metabolism , Deoxyribonucleosides , 9,10-Dimethyl-1,2-benzanthracene/analogs & derivatives , 9,10-Dimethyl-1,2-benzanthracene/metabolism , Animals , Benz(a)Anthracenes/analogs & derivatives , Benz(a)Anthracenes/metabolism , Cells, Cultured , Chemical Phenomena , Chemistry , Embryo, Mammalian , Mice , Spectrometry, Fluorescence , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
9,10-Dimethyl-1,2-benzanthracene , Benz(a)Anthracenes , Benz(a)Anthracenes/toxicity , DNA Repair/drug effects , 9,10-Dimethyl-1,2-benzanthracene/analogs & derivatives , 9,10-Dimethyl-1,2-benzanthracene/metabolism , 9,10-Dimethyl-1,2-benzanthracene/toxicity , Animals , Benz(a)Anthracenes/analogs & derivatives , Benz(a)Anthracenes/metabolism , Cells, Cultured , DNA/metabolism , Embryo, Mammalian , L Cells/drug effects , L Cells/metabolism , MiceABSTRACT
Previously, the 3,9-dihydroxy derivative of benz[a]-anthracene was shown to be weakly estrogenic. The availability of the related diol of the mammary carcinogen dimethylbenz[a]-anthracene, i.e., 3,9-dihydroxy-7,12-dimethylbenz[a]anthracene (3,9-diOHDMBA), prompted a similar study of its estrogenic properties. The competitive binding studies of 3,9-diOHDMBA with 17beta-estradiol in the uterine cytosol of immature SD rats gave a Ka of 1.7 x 10(8) M-1. 17beta-Estradiol (10(-9) M) binding to the 8S binding protein was inhibited by 3,9-diOHDMBA at concentrations similar to those of nafoxidine HCl (1 x 10(-5) M). Bioassay demonstrated that the diol possesses 1/4,464 the activity of 17beta-estradiol.
Subject(s)
9,10-Dimethyl-1,2-benzanthracene , Benz(a)Anthracenes , Estrogens , Receptors, Estrogen/metabolism , 9,10-Dimethyl-1,2-benzanthracene/analogs & derivatives , 9,10-Dimethyl-1,2-benzanthracene/metabolism , 9,10-Dimethyl-1,2-benzanthracene/pharmacology , Animals , Benz(a)Anthracenes/analogs & derivatives , Binding, Competitive , Cytosol/metabolism , Estradiol/metabolism , Female , In Vitro Techniques , Rats , Uterus/metabolismABSTRACT
The abilities of the racemic trans-3,4-, 5,6-, and 8,9-dihydrodiols of 7,12-dimethylbenz(a)anthracene to initiate skin tumors in mice were determined by using a two-stage system of tumorigenesis. The 7,12-dimethylbenz(a)anthracene trans-3,4-dihydrodiol was found to be much more active as a tumor initiator than the parent hydrocarbon. The 7,12-dimethylbenz(a)anthracene trans-5,6- and 8,9-dihydrodiols were essentially inactive as skin tumor initiators. Our results suggest that the 3,4-dihydrodiol of 7,12-dimethylbenz(a)anthracene is a proximal carcinogen and that the "bay region" diol-epoxide may be the ultimate carcinogenic form of DMBA.
Subject(s)
9,10-Dimethyl-1,2-benzanthracene , Benz(a)Anthracenes , Papilloma/chemically induced , Skin Neoplasms/chemically induced , 9,10-Dimethyl-1,2-benzanthracene/analogs & derivatives , 9,10-Dimethyl-1,2-benzanthracene/toxicity , Animals , Benz(a)Anthracenes/analogs & derivatives , Female , Mice , Neoplasms, Experimental/chemically induced , Structure-Activity Relationship , Tetradecanoylphorbol Acetate/administration & dosageABSTRACT
The skin tumor-initiating and V79 mutagenic activities of various derivatives of 7,12-dimethylbenz[a]anthracene (DMBA) were investigated to determine what possible cellular metabolite(s) may be responsible for its carcinogenicity and/or mutagenicity. 1-,2-,3-,4- and 5-hydroxyDMBA were found to be essentially inactive as skin tumor initiators whereas 9- and 10-hydroxyDMBA had weak activity. The (+/-)-trans DMBA 8,9- and 5,6-dihydrodiols were also essentially inactive as skin tumor initiators and (+/-)-DMBA 8beta,9alpha-diol-10alpha-11alpha-epoxide had weak skin tumor initiating activity. All of the above tested derivatives of DMBA were essentially inactive as mutagens in the cell-mediated or direct V79 mutagenesis systems. A methyl or fluoro addition to the 1, 2 or 5 positions almost completely blocked the skin tumor initiating and V79 mutagenic activities of DMBA, whereas a fluoro addition to position 11 did not. From our data we suggest that a 'bay region' diol-epoxide may be important in DMBA carcinogenicity and mutagenicity.
Subject(s)
9,10-Dimethyl-1,2-benzanthracene , Benz(a)Anthracenes , Carcinogens , Mutagens , Papilloma/chemically induced , Skin Neoplasms/chemically induced , 9,10-Dimethyl-1,2-benzanthracene/analogs & derivatives , 9,10-Dimethyl-1,2-benzanthracene/pharmacology , Animals , Benz(a)Anthracenes/analogs & derivatives , Drug Evaluation, Preclinical , Female , Glycols/pharmacology , Mice , Neoplasms, Experimental/chemically induced , Structure-Activity RelationshipSubject(s)
9,10-Dimethyl-1,2-benzanthracene , Benz(a)Anthracenes , Carcinogens , Mutagens , Papilloma/chemically induced , Skin Neoplasms/chemically induced , 9,10-Dimethyl-1,2-benzanthracene/analogs & derivatives , 9,10-Dimethyl-1,2-benzanthracene/metabolism , 9,10-Dimethyl-1,2-benzanthracene/pharmacology , Animals , Benz(a)Anthracenes/analogs & derivatives , Cells, Cultured , Female , Male , Mice , Neoplasms, Experimental/chemically induced , Structure-Activity RelationshipSubject(s)
9,10-Dimethyl-1,2-benzanthracene , Benz(a)Anthracenes , Mutagens , 9,10-Dimethyl-1,2-benzanthracene/analogs & derivatives , 9,10-Dimethyl-1,2-benzanthracene/metabolism , Animals , Benz(a)Anthracenes/analogs & derivatives , Biotransformation , Female , Glycols/metabolism , Microsomes, Liver/metabolism , Rats , Salmonella typhimurium/drug effects , Salmonella typhimurium/genetics , Structure-Activity RelationshipSubject(s)
9,10-Dimethyl-1,2-benzanthracene , Benz(a)Anthracenes , Flavonoids/pharmacology , Papilloma/chemically induced , Skin Neoplasms/chemically induced , 9,10-Dimethyl-1,2-benzanthracene/administration & dosage , 9,10-Dimethyl-1,2-benzanthracene/analogs & derivatives , 9,10-Dimethyl-1,2-benzanthracene/metabolism , Animals , Aryl Hydrocarbon Hydroxylases/antagonists & inhibitors , Benz(a)Anthracenes/analogs & derivatives , Female , Imidazoles/pharmacology , Mice , Neoplasms, Experimental/chemically induced , Papilloma/prevention & control , Quercetin/pharmacology , Skin/metabolism , Skin Neoplasms/prevention & controlABSTRACT
Statistical analysis of 361 cases of primary leukemia induced in outbred Long-Evans and Sprague-Dawley rats by 7,12-dimethylbenz[a]anthracene (DMBA) and 7,8,12-trimethylbenz[a]anthracene (TMBA) showed that the incidence of trisomy of chromosome No. 2 was significantly lower with TMBA (17.8%) than with DMBA (29.3%). This tendency was reproducible in both sexes. Another characteristic chromosome abnormality, long No. 2, was found in 10 cases (2.8%). Quinacrine fluorescence analysis revealed that cells with No. 2 trisomy or either of two types of long No. 2 had total and partial No. 2 trisomy, respectively. Other chromosome members of cells with long No. 2, as well as the chromosomes of cells with typical No. 2 trisomy and "normal diploid" leukemia cells, revealed no band abnormality. The phenotype of No. 2 trisomy, severe anemia of the hosts reported in DMBA-induced leukemias, was also noted in leukemias with TMBA-induced No. 2 trisomy but not in leukemias with long No. 2.
Subject(s)
9,10-Dimethyl-1,2-benzanthracene , Benz(a)Anthracenes , Chromosome Aberrations , Leukemia, Experimental/genetics , 9,10-Dimethyl-1,2-benzanthracene/analogs & derivatives , Anemia/complications , Anemia/genetics , Animals , Benz(a)Anthracenes/analogs & derivatives , Female , Fluorescence , Leukemia, Experimental/chemically induced , Leukemia, Experimental/complications , Male , Quinacrine , Rats , TrisomyABSTRACT
Inosine was reacted with phenanthrene-9,10-oxide and 7,12-dimethylbenz(a)anthracene-5,6-oxide (DMBA-5,6-oxide) to yield the corresponding N-1-alkylinosines. They were shown to undergo hydrolysis to 5-amino-4-imidazole-N-alkylcarboxamide ribosides when heated in the presence of sodium carbonate. Guanosine was reacted with DMBA-5,6-oxide to yield a mixture of N-7-alkylguanines along with a smaller amount of an orcine positive product exhibiting an ultraviolet spectrum resembling that of DMBA-5,6-dihydrodiol.
Subject(s)
9,10-Dimethyl-1,2-benzanthracene , Benz(a)Anthracenes , Guanosine/metabolism , Inosine/metabolism , Phenanthrenes/metabolism , 9,10-Dimethyl-1,2-benzanthracene/analogs & derivatives , 9,10-Dimethyl-1,2-benzanthracene/metabolism , Alkylation , Benz(a)Anthracenes/analogs & derivatives , Chemical Phenomena , Chemistry , Guanosine/analogs & derivatives , In Vitro Techniques , Inosine/analogs & derivativesABSTRACT
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.
Subject(s)
9,10-Dimethyl-1,2-benzanthracene , Benz(a)Anthracenes , Carcinogens , Lung Neoplasms/chemically induced , 9,10-Dimethyl-1,2-benzanthracene/analogs & derivatives , 9,10-Dimethyl-1,2-benzanthracene/metabolism , 9,10-Dimethyl-1,2-benzanthracene/toxicity , Adenocarcinoma/chemically induced , Adenoma/chemically induced , Animals , Benz(a)Anthracenes/analogs & derivatives , Cell Transformation, Neoplastic , Female , In Vitro Techniques , Mice , Mice, Inbred BALB C , Neoplasm Transplantation , Neoplasms, Experimental/chemically induced , Transplantation, IsogeneicABSTRACT
The molecular structure and conformation of the cis-5,6-dihydrodiol of 7,12-dimethylbenz[a]anthracene has been determined by an X-ray crystallographic analysis. The compound crystallizes in the space group P21/a with cell dimensions a equals 17.799(6), b equals 33.211(8), c equals 5.241(1) A, beta equals 91.88(2)degrees. There are two molecules, designated A and B in the asymmetrical unit, that are not related to each other by crystallographic symmetry. Their conformations are almost identical, and there are no significant differences in their bond lengths or angles. In both molecules the 5-hydroxyl group is equatorial while the 6-hydroxyl group is axial. This conformation is probably forced by steric hindrance between the hydroxyl group, 0-6, and the hydrogen atoms of the 7-methyl group. The molecules pack in the crystal by forming hydrogen bonds between the hydroxyl groups of adjacent molecules, A with A, B, with B, and A with B. The ring system of the cis-5,6-dihydrodiol is much more buckled than is that in 7,12-dimethylbenz[a]anthracene itself. The angle between the two outermost rings is 36 degrees, the deviation from planarity being primarily a consequence of the partial saturation in the ring containing the two hydroxyl groups. Extrapolation of these results to other dihydrodiol derivatives of carcinogenic hydrocarbons permits some predictions of preferred molecular geometry. Thus, the 8,9-dihydrodiol-10,11-epoxide of 7,12-dimethylbenz]a[anthracene, analogous to the biologically active 7,8-dihydrodiol-9,10-epoxide of benzo]a[pyrene, a mutagen that is believed to be an active intermediate in carcinogenesis by benzo]a[pyrene, should probably exist preferentially in a conformation bearing the8-hydroxyl group in the axial orientation.
Subject(s)
9,10-Dimethyl-1,2-benzanthracene , Benz(a)Anthracenes , 9,10-Dimethyl-1,2-benzanthracene/analogs & derivatives , 9,10-Dimethyl-1,2-benzanthracene/metabolism , Benz(a)Anthracenes/analogs & derivatives , Chemical Phenomena , Chemistry , Crystallography , Molecular Conformation , Stereoisomerism , X-Ray DiffractionABSTRACT
The 8,9-dihydrodiols of 7-methylbenz(a)anthracene and 7,12-dimethylbenz(a)anthracene and the 7,8-dihydrodiol of benzo(a)pyrene, which are non-K-region diols with adjacent olefinic double bonds that can be metabolized to diol-epoxides, were more active than the parent hydrocarbons in inducing malignant transformation of M2 mouse fibroblasts; a fourth non-K-region diol, the 9,10-dihydrodiol of benzo(a)pyrene was less active than benzo(a)pyrene. The related K-region dihydrodiols, which lack adjacent olefinic double bonds, and 6-hydroxybenzo(a)pyrene were inactive, 7,8-Dihydrobenzo(a)pyrene, a more potent carcinogen than the 9,10 isomer, induced malignant transformation, but the 9,10 isomer was inactive. Transformed cells with abnormal morphology yielded sarcomas on injection into isologous mice; treated but morphologically normal cells did not. These results support the role of diols and diol-epoxides in the metabolic activation of polycyclic hydrocarbons.
Subject(s)
9,10-Dimethyl-1,2-benzanthracene/analogs & derivatives , Benz(a)Anthracenes/analogs & derivatives , Benzopyrenes , Cell Transformation, Neoplastic , Glycols , Animals , Cells, Cultured , Fibroblasts/drug effects , Mice , Sarcoma, Experimental/etiologySubject(s)
9,10-Dimethyl-1,2-benzanthracene/analogs & derivatives , Benz(a)Anthracenes/analogs & derivatives , Nucleosides/isolation & purification , 9,10-Dimethyl-1,2-benzanthracene/isolation & purification , 9,10-Dimethyl-1,2-benzanthracene/metabolism , Animals , Chromatography, High Pressure Liquid/methods , Male , Microsomes, Liver/metabolism , Poly A/metabolism , Poly G/metabolism , RatsABSTRACT
The influence of two metabolites of 7,12-dimethylbenz(a)anthracene (DMBA)--7-hydromethyl-12-methylbenz(a)anthracene and 7,12-dihydroxymethylbenz(a)anthracene--on the dynamics of DMBA fluorescence was studied in the skin of mice. The first of the metabolites did not affect the dynamics of DMBA fluorescence, whereas the second one, when used in equimolar concentrations with DMBA, prolonged the duration of DMBA fluorescence in the skin. The same effect was observed in case of 7,8-benzoflavone, and inhibitor of DMBA metabolism.
Subject(s)
9,10-Dimethyl-1,2-benzanthracene , Benz(a)Anthracenes , Fluorescence , Skin/drug effects , 9,10-Dimethyl-1,2-benzanthracene/analogs & derivatives , Animals , Benz(a)Anthracenes/analogs & derivatives , Female , Mice , Mice, NudeABSTRACT
Benz(a)anthracene, 7,12-dimethylbenz(a)anthracene, dibenz(a)anthracene and benzo(a)pyrene and their related "K region" epoxides were tested for carcinogenic activities using a system in which mouse lung tissue was incubated in the presence of the test compound for 30 min and then implanted into isologous mice. Only 7,12-dimethylbenz(a)anthracene showed any marked carcinogenic activity under the conditions used, but all the compounds tested produced extensive proliferative outgrowths in the implanted tissues that may represent specific responses to the carcinogens.
Subject(s)
9,10-Dimethyl-1,2-benzanthracene/analogs & derivatives , 9,10-Dimethyl-1,2-benzanthracene/toxicity , Benz(a)Anthracenes/analogs & derivatives , Benz(a)Anthracenes/toxicity , Benzopyrenes/toxicity , Lung Neoplasms/chemically induced , Adenocarcinoma/chemically induced , Adenocarcinoma, Bronchiolo-Alveolar/chemically induced , Adenoma/chemically induced , Animals , Female , In Vitro Techniques , Lung Neoplasms/pathology , Lung Transplantation , Mice , Mice, Inbred BALB C , Transplantation, IsogeneicABSTRACT
The comparative carcinogenic activities of 7,12-dimethylbenz(a)anthracene 5,6-oxide (DMBA-5,6-oxide) and 7,12-dimethylbenz(a)anthracene (DMBA) to skin and subcutaneous tissue were studied. It was found that DMBA-5,6-oxide was less carcinogenic to both the skin and subcutaneous tissue, than DMBA. Moreover it does not show any significant initiating acitivity. The results are discussed.
