7,12-Dimethylbenz[a]anthracene

About: 7,12-Dimethylbenz[a]anthracene is a research topic. Over the lifetime, 1717 publications have been published within this topic receiving 40892 citations.

Studies on the anti-tumor-promoting activity of naturally occurring substances. IV. Pd-II [(+)anomalin, (+)praeruptorin B], a seselin-type coumarin, inhibits the promotion of skin tumor formation by 12-O-tetradecanoylphorbol-13-acetate in 7,12-dimethylbenz[a]anthracene-initiated mice.

Abstract: Since Pd-II [(+)anomalin, (+)praeruptorin B], a seselin-type coumarin, was found to inhibit tumor promoter induced phenomenon in vitro, the effect of Pd-II on the in vivo tumor-promoting action of 12-O-tetradecanoylphorbol-13-acetate (TPA) in 7,12-dimethylbenz[a]anthracene-initiated mouse skin was investigated. Pd-II, applied 40 min before the TPA treatment, at a dose of 10 mumol/painting, completely suppressed tumor formation up to 20 weeks of tumor promotion, without any toxicity. Besides Pd-II, various anti-tumor-promoter coumarins were found in the traditional Chinese medicine Qian-Hu, from which Pd-II was obtained. These coumarins may be useful for the development of an effective method to prevent cancer.

Decreased 7,12-dimethylbenz[a]anthracene-induced carcinogenesis coincides with the induction of antitumor immunities in adult female B6C3F1 mice pretreated with genistein

Abstract: The objective of this study was to determine if genistein (GEN) modulation of the immune responses might contribute to the increased host resistances to tumors. A time-course study was performed in adult female B6C3F1 mice that had been exposed to GEN for 1-4 weeks at the dose level of 20 mg/kg by gavage. A significant increase in ex vivo cytotoxic T lymphocyte (CTL) activity was observed in the periods of 2 weeks and 4 weeks. Moreover, increased activities of CTLs were associated with a decrease in the percentage of CD4 + CD25 + T cells and an increase in the production of interferon-γ and activation of STAT1 (signal transducer and activator of transcription 1) and STAT4. Additionally, exposure of mice to GEN increased the activities of in vivo CTLs. An increased activity of natural killer (NK) cells was also observed. Further study in the B16F10 tumor model suggested that GEN-mediated enhancement in host resistance to B16F10 tumor was partially related to its potentiating effect on NK cells. Finally, 7,12-dimethylbenz[a]anthracene (DMBA)-induced tumor model was employed to determine the chemopreventive effect of oral GEN treatment. Mice pretreated with GEN for 2 weeks by gavage, the time when an enhanced CTL activity had been produced, had a decreased susceptibility toward DMBA-mediated carcinogenesis, while treatment with GEN after tumor induction conferred no protection. In conclusion, pretreatment with GEN by gavage could enhance host resistances to the B16F10 tumor and DMBA-induced carcinogenesis, suggesting that GEN modulation of immune response was, at least partially, responsible for the antitumor effect of this compound.

Induction of mammary cytochromes P-450: an essential first step in the metabolism of 7,12-dimethylbenz[a]anthracene by rat mammary epithelial cells.

Abstract: Rat mammary epithelial cells (RMEC) in culture have been shown to activate polycyclic aromatic hydrocarbon (PAH) carcinogens. This study investigates the role of mammary cytochrome P-450 monooxygenases in these metabolic processes. Monooxygenation of 7,12-dimethylbenz[a]anthracene (DMBA) by RMEC in culture exhibited a 6-h lag period before reaching a constant rate. The mechanism for this time-dependent expression of DMBA monooxygenase activity was investigated in lysed cells, where both conjugation and in situ induction of P-450 are prevented. Although metabolism of DMBA by untreated RMEC lysates was undetectable (less than 1 pmol/mg cell protein/h), prior exposure of cultured cells to benz[a]anthracene (BA) induced DMBA metabolism, (approximately 100 pmol/mg cell protein/h). BA pretreatment also eliminated the lag period for metabolism of DMBA by cultured RMEC but did not prevent additional induction of DMBA monoxygenase activity by the substrate. The distribution of monooxygenated DMBA metabolites formed by BA-induced cell lysates was clearly different from that obtained with purified P-450c, the predominant PAH-inducible isozyme in rat liver. For example, the carcinogen precursor DMBA 3,4-dihydrodiol, which is not formed by P-450c, was a clearly detectable product in RMEC. The low epoxide hydratase activity of BA-induced lysate (approximately 400-fold lower compared to that in the liver) limited formation of all DMBA dihydrodiols. The formation of DMBA 3,4-dihydrodiol increased by 5-fold following addition of exogenous purified epoxide hydratase. The DMBA monooxygenase activity of BA-induced RMEC lysates was completely inhibited by alpha-naphthoflavone but was only partially inhibited (50%) by a polyclonal antibody raised against cytochrome P-450c. Anti P-450c completely inhibited formation of some of the metabolites, partially inhibited formation of others and notably stimulated formation of DMBA 3,4-dihydrodiol by 60%. A polyclonal antibody that recognized both rat hepatic P-450a and a group of P-450 isozymes related to P-450h, and which totally inhibited DMBA 3,4-dihydrodiol formation by rat liver microsomes, did not inhibit formation of any DMBA metabolite in RMEC, including DMBA 3,4-dihydrodiol. Western blot analyses of RMEC homogenates demonstrated that BA pretreatment induces P-450c, but not P-450a or any of the P-450h-related isozymes. We conclude that metabolism of DMBA by RMEC depends on induction of P-450c and at least one additional form of cytochrome P-450 which is immunochemically distinct from rat hepatic P-450a and P-450h related isozymes, but is sensitive to alpha-naphthoflavone.

Chemopreventive efficacy and anti-lipid peroxidative potential of Jasminum grandiflorum Linn. on 7,12-dimethylbenz(a)anthracene-induced rat mammary carcinogenesis.

Abstract: The aim of this study was to investigate the chemopreventive efficacy and anti-lipid peroxidative potential of Jasminum grandiflorum Linn. on 7,12-dimethylbenz(a)anthracene (DMBA)-induced rat mammary carcinogenesis. Mammary tumors were developed by a single subcutaneous injection of 25 mg DMBA in 1 mL emulsion of sunflower oil and physiological saline. The tumor incidence and tumor volume that formed in the breast were determined. Oral administration of ethanolic extract of J. grandiflorum flowers (JgEt) at a dose of 300 mg/kg body weight for 14 weeks to DMBA-injected animals completely prevented the formation of tumors in the pre-initiation period. JgEt also exerted significant anti-lipid peroxidative effect and improved the antioxidant defense system in DMBA-treated rats. The results of this study clearly indicate that JgEt has potent chemopreventive efficacy in experimental mammary carcinogenesis and further studies are warranted to isolate and characterize the bioactive principle from JgEt.

DNA adduct formation and molecular analysis of in vivo lacI mutations in the mammary tissue of Big Blue rats treated with 7, 12-dimethylbenz[a]anthracene.

Abstract: Recently we compared the lacI and Hprt mutant frequencies (MFs) and types of mutations in lymphocytes of Big Blue((R)) (BB) rats exposed to 7,12-dimethylbenz[a]anthracene (DMBA) under conditions that result in mammary gland tumors. In this study, we have examined the target mammary tissue for DMBA-induced DNA adducts, lacI MF and types of lacI mutations. Seven-week-old female BB rats were given single doses of 0, 20 or 130 mg/kg DMBA by gavage and the DNA adducts and lacI MFs in the mammary tissue were measured over a period of 14 days and 18 weeks, respectively, following treatment. The lacI MF in the mammary tissue increased for 10 weeks and then remained relatively constant; 130 mg/kg DMBA produced a 14-fold increase in the MF (255 +/- 50 x 10(-6) p.f.u.) over control MF (18. 3 +/- 4 x 10(-6) p.f.u.). (32)P-post-labeling analysis of DNA from mammary tissue and splenic lymphocytes of treated rats revealed two major adducts. Comparison of these adducts with DMBA standards indicated that the adducts formed by DMBA involved both G:C and A:T base pairs. DNA sequencing revealed that the majority of DMBA-induced lacI mutations were base pair substitutions and that A:T-->T:A (44% of the independent mutations) and G:C-->T:A (24% of the independent mutations) transversions were the predominant types. Furthermore, the mutational results revealed a 'hotspot' for a G-->T mutation in codon 95 (GTG-->TTG) of the lacI gene in mammary tissue. These results suggest that DMBA is highly mutagenic to lacI in mammary tissue and that adducts with both G:C and A:T base pairs participate in forming mutations in DMBA-treated BB rats.