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.

Induction of mouse epidermal ornithine decarboxylase activity and skin tumors by 7, 12-dimethylbenz[a]anthracene: modulation by retinoic acid and 7,8-benzoflavone

Abstract: Application of a single large dose (3.6 micromol) or smaller weekly repeated doses (0.2 micromol) of 7,12-dimethylbenz[a]anthracene (DMBA) to the skin of CD-1 mice led to a 20 to 50-fold increase in epidermal ornithine decarboxylase (ODC) (EC 4.1.1.17) activity as well as tumor formation. Retinoic acid (0.17-68 nmol), a potent inhibitor of both the induction of ODC activity and tumor formation by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA), failed to inhibit both the induction of ODC activity and tumor formation by DMBA. In contrast, 7,8-benzoflavone (367 nmol), which did not inhibit the induction of ODC activity by TPA, effectively inhibited the induction of ODC activity as well as the formation of skin tumors caused by DMBA. These results indicate that (a) the mechanism of the induction of ODC activity and tumor formation by a complete carcinogen appears to be different from that of the tumor promoter TPA, (b) DMBA-induced ODC activity may be an important component of the mechanism of DMBA carcinogenesis, and (c) the protective effect of retinoic acid on skin carcinogenesis is not universal; it inhibits skin tumor formation by some agents and not by others.

Identification of four trans-3,4-dihydrodiol metabolites of 7,12-dimethylbenz[a]anthracene and their in vitro DNA-binding activities upon further metabolism.

Abstract: Trans-3,4-dihydrodiols of 7,12-dimethylbenz[a]anthracene (7,12-Me2BA), 7-methyl-12-hydroxymethylbenz[a]anthracene (7-Me-12-OHMeBA), 7-hydroxymethyl-12-methylbenz[a]anthracene (7-OHMe-12-MeBA), and 7,12-di(hydroxymethyl)benz[a]anthracene [7,12-(OHMe)2BA] have been identified as metabolites of the potent carcinogenic and adrenocorticolytic agent 7,12-MeBA. The four trans-3,4-dihydrodiols were identified by their (i) ultraviolet-visible absorption and fluorescence properties, (ii) different retention times on both reversed-phase and normal-phase high-pressure liquid chromatography, (iii) mass spectral analysis, and (iv) inability to form vicinal cis-acetonides. Upon further metabolism by liver microsomes, the trans-3,4-dihydrodiols of 7,12-Me2BA, 7-Me-12OHMeBA, and 7-OHMe-12-MeBA were found to give rise to products that bind more strongly to DNA in vitro than do the products of 7,12-Me2BA. The evidence suggests that one or more of the four trans-3,4-dihydrodiols may be the proximate carcinogenic and adrenocorticolytic metabolites.

Growth factor binding to 7,12-dimethylbenz(a)anthracene-induced mammary tumors from rats subject to chronic caloric restriction.

Abstract: Caloric restriction (CR) inhibits tumorigenesis in rodents. To understand the basis for this effect the binding of insulin, insulin-like growth factor I/somatomedin C (IGF-I/Sm-C), insulin-like growth factor II/multiplication stimulating activity (IGF-II/MSA), and epidermal growth factor were examined to membrane preparations of 7,12-dimethylbenz(a)anthracene-induced mammary adenocarcinomas and several normal tissues from female Sprague-Dawley rats. Animals were fed ad libitum (AL) or 25% and 40% calorically restricted diets. Large, palpable (LP) and small, less than or equal to 100 mg, nonpalpable (SNP) tumors were evaluated. Growth factor binding to tumors was differentially affected by CR. IGF-I/Sm-C binding was comparable for AL-LP, AL-SNP, and 25% CR-LP tumors, but elevated in 25% CR-SNP tumors. Scatchard analysis revealed high and low affinity IGF-I/Sm-C binding sites, with AL-SNP and 25% CR-SNP tumors exhibiting similar levels of high affinity sites and at a greater concentration than AL-LP and 25% CR-LP tumors. Insulin binding to mammary tumors was low, i.e., 8- to 13-fold lower than IGF-I/Sm-C binding. The 25% CR-LP and SNP tumors bound 2- to 5-fold more insulin than corresponding AL-LP and SNP tumors. Binding of IGF-II/MSA to these tumor preparations was high, approximately 11- to 25-fold greater than insulin binding, and was unaffected by CR or tumor size. The binding of epidermal growth factor was not detected in any tumor preparations. Receptor binding studies were confirmed with covalent cross-linking and sodium dodecyl sulfate-polyacrylamide gel electrophoresis analyses. Normal tissues exhibited tissue- and growth factor-specific alterations in binding with host CR. Thus, alterations in growth factor binding were not tumor specific, but were less pronounced than in mammary tumors. These findings suggest alterations in IGF-I/Sm-C and insulin binding properties to tumors in relation to CR and tumor size may contribute, in part, to the inhibitory effects of CR on tumorigenesis.

Naturally occurring coumarins inhibit 7,12-dimethylbenz[a]anthracene DNA adduct formation in mouse mammary gland.

Abstract: Naturally occurring coumarins (NOCs) are anti-carcinogenic in the mouse skin model. To characterize the chemopreventive potential of NOCs against breast cancer, we first examined their effects on 7,12-dimethylbenz[a]anthracene (DMBA)-DNA adduct formation in mouse mammary gland. We hypothesized that those NOCs that both inhibited cytochrome P450 1A1/1B1 and induced hepatic glutathione S-transferases (GSTs) would be the most effective in blocking DMBA-DNA adduct formation in mouse mammary gland. To address this hypothesis, simple coumarins (e.g. coumarin and limettin, which induced mouse hepatic GSTs but had little effect on P4501A1/1B1) and linear furanocoumarins (e.g. imperatorin and isopimpinellin, which induced hepatic GSTs and were potent inhibitors of P4501A1/1B1) were compared. Mice were pretreated with NOCs (150 mg/kg body wt, by gavage) prior to either a single dose of DMBA (50 microg) or multiple doses of DMBA (20 microg daily for 3 and 6 weeks). Mammary DMBA-DNA adduct formation was quantitated by the nuclease P1-enhanced 32P-postlabeling assay. With the single dose of DMBA, coumarin, limettin, imperatorin and isopimpinellin inhibited DMBA-DNA adduct formation by 50, 41, 79 and 88%, respectively. Coumarin, limettin and imperatorin blocked DMBA-DNA adduct formation by 36, 60, and 66% at 3 weeks, and by 0, 49 and 55% at 6 weeks of DMBA dosing, respectively. In a 6 week dose-response study of select NOCs and 7,8-benzoflavone (a potent P4501 inhibitor that had little effect on GSTs), DMBA-DNA adduct formation was inhibited by 0, 43 and 24% in the limettin groups; by 26, 26 and 69% in the isopimpinellin groups; and by 80, 96 and 97% in the 7,8- benzoflavone groups at 35, 70 and 150 mg/kg, respectively. Taken together, these results suggest that linear furanocoumarins had a greater inhibitory effect on DMBA-DNA adduct formation in mouse mammary glands compared with simple coumarins, and that the predominant effect may be P4501 inhibition.

Inhibitory effects of naturally occurring coumarins on the metabolic activation of benzo[a]pyrene and 7,12-dimethylbenz[a]anthracene in cultured mouse keratinocytes.

Abstract: Several naturally occurring coumarins to which humans are routinely exposed have been previously found to be potent inhibitors and inactivators of cytochrome P450 (P450) 1A1-mediated monooxygenase in both murine hepatic microsomes and in a reconstituted system using purified human P450 1A1 [Cai et al. (1993) Chem. Res. Toxicol., 6, 872-879 and Cai et al. (1996) Chem. Res. Toxicol., 9, 729-736]. In the present study, several of these coumarins were investigated for their inhibitory effects on the metabolism and metabolic activation of benzo[a]pyrene (B[a]P) and 7,12-dimethylbenz[a]anthracene (DMBA) in cultured mouse keratinocytes. Initial analysis of B[a]P metabolism in cultured keratinocytes showed that imperatorin, isoimperatorin, coriandrin, and bergamottin, at concentrations of 2 nM equal with B[a]P, reduced the formation of water-soluble metabolites of B[a]P by 33% to 57%. Bergamottin and coriandrin were the most potent inhibitors of the compounds examined. HPLC analysis of organic solvent-soluble metabolites of B[a]P indicated that all the coumarins tested significantly reduced the formation of individual B[a]P metabolites (including phenols, diols and tetraols). However, the greatest effect was on the formation of B[a]P tetraols. Additional experiments determined the ability of selected coumarins to block covalent binding of B[a]P and DMBA to DNA in keratinocytes. Bergamottin preferentially inhibited the binding of B[a]P to DNA by 56%, while coriandrin preferentially inhibited the binding of DMBA to DNA by 48%. Notably, analysis of individual DNA adducts formed from B[a]P and DMBA indicated that both bergamottin and coriandrin specifically inhibited the formation of anti diol-epoxide DNA adducts derived from both hydrocarbons. The preferential inhibitory effect of bergamottin and coriandrin on the formation of anti diol-epoxide adducts derived from DMBA was further confirmed by separation of anti- and syn-diol-epoxide-DNA adducts using immobilized boronate chromatography. The current study demonstrates that certain naturally occurring coumarins inhibited metabolic activation of B[a]P and DMBA in cultured mouse keratinocytes and specifically inhibited the formation of DNA adducts derived from the anti diol-epoxide diastereomers from either hydrocarbon. The current data also suggest that certain naturally occurring coumarins may possess anticarcinogenic activity toward polycyclic aromatic hydrocarbons.