US20110155157A1 - Cigarette filter containing rosemary extract and a method of reducing dna damage caused by harmful agents in cigarette smoke by use of said filter - Google Patents

Cigarette filter containing rosemary extract and a method of reducing dna damage caused by harmful agents in cigarette smoke by use of said filter Download PDF

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US20110155157A1
US20110155157A1 US12/515,040 US51504009A US2011155157A1 US 20110155157 A1 US20110155157 A1 US 20110155157A1 US 51504009 A US51504009 A US 51504009A US 2011155157 A1 US2011155157 A1 US 2011155157A1
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bpde
filter
cigarette
cigarette smoke
dna
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Iman Emami
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    • A—HUMAN NECESSITIES
    • A24—TOBACCO; CIGARS; CIGARETTES; SIMULATED SMOKING DEVICES; SMOKERS' REQUISITES
    • A24D—CIGARS; CIGARETTES; TOBACCO SMOKE FILTERS; MOUTHPIECES FOR CIGARS OR CIGARETTES; MANUFACTURE OF TOBACCO SMOKE FILTERS OR MOUTHPIECES
    • A24D3/00—Tobacco smoke filters, e.g. filter-tips, filtering inserts; Filters specially adapted for simulated smoking devices; Mouthpieces for cigars or cigarettes
    • A24D3/06—Use of materials for tobacco smoke filters
    • A—HUMAN NECESSITIES
    • A24—TOBACCO; CIGARS; CIGARETTES; SIMULATED SMOKING DEVICES; SMOKERS' REQUISITES
    • A24B—MANUFACTURE OR PREPARATION OF TOBACCO FOR SMOKING OR CHEWING; TOBACCO; SNUFF
    • A24B15/00—Chemical features or treatment of tobacco; Tobacco substitutes, e.g. in liquid form
    • A24B15/18—Treatment of tobacco products or tobacco substitutes
    • A24B15/28—Treatment of tobacco products or tobacco substitutes by chemical substances
    • A24B15/30—Treatment of tobacco products or tobacco substitutes by chemical substances by organic substances
    • A—HUMAN NECESSITIES
    • A24—TOBACCO; CIGARS; CIGARETTES; SIMULATED SMOKING DEVICES; SMOKERS' REQUISITES
    • A24D—CIGARS; CIGARETTES; TOBACCO SMOKE FILTERS; MOUTHPIECES FOR CIGARS OR CIGARETTES; MANUFACTURE OF TOBACCO SMOKE FILTERS OR MOUTHPIECES
    • A24D3/00—Tobacco smoke filters, e.g. filter-tips, filtering inserts; Filters specially adapted for simulated smoking devices; Mouthpieces for cigars or cigarettes
    • A24D3/06—Use of materials for tobacco smoke filters
    • A24D3/14—Use of materials for tobacco smoke filters of organic materials as additive

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  • the invention relates to a cigarette filter containing rosemary extract and a method of reducing DNA damage caused by various harmful agents in cigarette smoke. More specifically, the present invention relates to the use of said filter to reduce DNA damage caused by benzo(a)pyrenes in human cells by the reduction of the human lung benzo(a)pyrene diol epoxide-dG (BPDE-dG) adduct.
  • BPDE-dG human lung benzo(a)pyrene diol epoxide-dG
  • BPDE-dG human lung benzo(a)pyrene diol epoxide-dG adduct concentrates in bronchial cells. This adduct now is recognized as a critical event in tumorigenesis by benzo(a)pyrenes. Cigarette smoke is a significant contributor to BPDE-dG formation.
  • Benzo(a)pyrene is a highly carcinogenic polycyclic aromatic hydrocarbon (PAH) present in emission exhausts, charbroiled food and in small quantity in cigarette smoke, typically less than 10 ng per cigarette.
  • PAH polycyclic aromatic hydrocarbon
  • BP is one of more than 60 carcinogens in cigarette smoke that is involved in the aetiology of lung cancer.
  • BPDE benzo(a)pyrene-7,8-diol-9,10-epoxide
  • BPDE benzo(a)pyrene-7,8-diol-9,10-epoxide
  • BPDE-dG benzo(a)pyrene-7,8-diol-9,10-epoxide-N 2 -deoxyguanosine
  • Rosemary Roamarinus officinalis Labiatae herb and oil, rosemary extracts, carnosic acid and carnosol are commonly used as spice and flavoring agents in food processing for their desirable flavor and high antioxidant activity.
  • BP is considered to be a significant carcinogen involved in lung cancer induction in smokers and, as is shown in this study, reactive oxygen species contribute substantially in the formation of the critical lung tumorigenic adduct. While it is both critical to prevent addiction to tobacco and to enhance the efficacy of smoking cessation and reduction programs, these approaches have had little impact.
  • the prevention of the formation of BPDE-dG adduct is one approach which may lead to decreasing lung cancer risk in addicted smokers.
  • the invention relates to a cigarette filter containing rosemary extract and a method of reducing DNA damage caused by harmful agents in cigarette smoke. More specifically, the present invention provides for the use of said filter to reduce DNA damage caused by benzo(a)pyrenes in human cells by the reduction of the human lung benzo(a)pyrene diol epoxide-dG (BPDE-dG) adduct.
  • BPDE-dG human lung benzo(a)pyrene diol epoxide-dG
  • Cigarette smoke thus may in this way responsible for the formation of the critical lung tumorigenic adduct.
  • modified cigarette filter containing rosemary extract decreases by more than 70% of the BPDE-dG adducts level due to the cigarette smoke in MCF-7 cells. This discovery, I believe is a significant advance in decreasing lung cancer risk in addicted smokers.
  • FIG. 1 Principal metabolic pathway and DNA binding of the carcinogen benzo(a)pyrene.
  • Benzo(a)pyrene is a tobacco carcinogen that may be converted in vivo enzymatically or by oxygen reactive species to yield DNA-reactive dihydrodiol epoxides.
  • Stereoselective generation of the mutagenic (+)-r-7,t-8-dihydroxy-t-9,10-oxy-7,8,9,10-tetrahydro-BP [(+)-anti-BPDE] from ( ⁇ )-BP-7,8-dihydrodiol is catalyzed by cytochrome-P450-dependent monooxygenases (P450) or reactive oxygen species.
  • P450 cytochrome-P450-dependent monooxygenases
  • FIG. 2 Results obtained by using a cell-free system concomitant with DNA adduction: 6 mg calf thymus DNA in 2 ml water was added to 5 ml CSS with different dilutions and reacted for 2 hours at room temperature with (+)-BP-7,8-diol (final concentration 3.6 ⁇ M). DNA was hydrolyzed and the released BP-tetrol I were measured as outlined in Materials and Methods.
  • FIG. 3 (a) Stereochemistry of BP-7,8-diol epoxidation by peroxyl radicals and cytochrome P450 to reactive species (anti-BPDE and syn-BPDE) that can bind to DNA, and (b) acid hydrolysis of DNA to BP-tetrols measured in this study.
  • the hydrolysis of ( ⁇ )-anti-BPDE-dG and ( ⁇ )-syn-BPDE leads to the formation of BP-tetrol 1-2 and BP-tetrol II-1 which however are unstable and are converted into BP-tetrol I-1 and BP-tetrol 11-2.
  • FIG. 4 Results obtained using MFC-7 cells. 10 ⁇ 10 6 cells/150 cm 2 flask in a total volume of 20 ml were treated for 2 hrs with (+)-BP-7,8-diol (0.2 ⁇ M) alone or in presence of different dilutions of CSS DNA was isolated, hydrolyzed and the released BP-tetrols were measured and the binding levels determined as outlined in Materials and Methods. Two distinct peaks were observed on the chromatograms corresponding to BP-tetrol I and BP-tetrol II derived from ( ⁇ )-anti-BPDE-dG and (+)-syn-BPDE-dG respectively (refs. 32-34).
  • FIG. 4 a upper panel, increases of ( ⁇ )-anti-BPDE-dG adducts with CSS dilution
  • FIG. 4 b lower panel, increases of 1/(+)-syn-BPDE-dG adduct with CSS dilution.
  • FIG. 5 BPDE-dG binding in MCF-7 cells after exposure to BP 2.5 ⁇ M or BP 2.5 CS solution (dilution 20 times) for the time indicated. Cigarette smoke solution was added the last 2 hours during the exposure to BP (Scheme 1). Analysis of BPDE-dG was performed as described in Materials and Methods. Values represent the means of two independent experiments with 4-6 HPLC runs plus Standard. The BPDE-dG value were 11.7 ⁇ 0.5 (mean ⁇ s.d.) ⁇ g of adducts per mg DNA after 12 hours of incubation and 17.6 ⁇ 0.4, 26.1 ⁇ 0.9 after hours and 24 hours respectively.
  • the CYP spontaneous metabolism increased theses values to 17.2 ⁇ 0.5, 27.8 ⁇ 0.8 and 42.2 ⁇ 1.0 two hours after the reference time at 12, 18 and 24 hours respectively.
  • the addition of cigarette smoke solution (CSS) induced a much more dramatic change during the same two hours period leading to a final BPDE-dG value of 36.9 ⁇ 1.2, 56.7 ⁇ 0.9 and 80.2 ⁇ 1.2 (mean ⁇ s.d.) ⁇ g of adducts per mg after 12, 18 and 24 hours respectively.
  • FIG. 6 BPDE-dG binding in MCF-7 cells after exposure to BP 2.5 ⁇ M or BP 2.5 ⁇ M CS solution obtained from standard filter and filter containing rosemary extract. The cigarette smoke solution was added for the last 2 hours during the exposure to BP for the time indicated (Scheme 1). Analysis of BPDE-dG was performed as described in Materials and Methods. The HPLC runs show that there is only one peak on chromatograms which correspond to BP-tetrol I derived from (+)-anti-BPDE-dG. Values represent the means of two independent experiments with 4-6 HPLC runs plus Std.
  • the standard CSS system includes 2 ml calf thymus DNA (3 mg/ml), 600 ⁇ l 30 ⁇ M (+) BaP-7,8-diol and 5 ml of diluted CSS with PBS (1:19) at pH 7.4, and was incubated at room temperature for 2 h. Each value was obtained from three independent experiments performed in duplicate. The average error was about 12% in each duplicate experiment.
  • the BPDE-dG value of the standard was 56 ⁇ 6.3 (mean ⁇ s.d.) adducts per mg DNA.
  • Cigarette smoking is causally associated with a large number of human cancers. Tobacco use is by far the most widespread link between exposure to known carcinogens and death from cancer, and is therefore a model for understanding mechanisms of cancer induction.
  • Benzo(a)pyrene is a highly carcinogenic polycyclic aromatic hydrocarbon (PAH) present in emission exhausts, charbroiled food and in small quantity in cigarette smoke, typically less than 10 ng per cigarette.
  • PAH polycyclic aromatic hydrocarbon
  • BP is one of more than 60 carcinogens in cigarette smoke that is involved in the aetiology of lung cancer. It is metabolically activated into benzo(a)pyrene-7,8-diol-9,10-epoxide (BPDE) which reacts with DNA predominantly at the N 2 -position of guanine to produce primarily N 2 -guanine lesions, e.g. benzo(a)pyrene-7,8-diol-9,10-epoxide-N 2 -deoxyguanosine (BPDE-dG) adduct.
  • PAH polycyclic aromatic hydrocarbon
  • BPDE-DNA adducts in human tissues has been conclusively established and BPDE-dG adduct concentrated exclusively in bronchial cells and is thus implicated in the initiation of human lung cancer.
  • This carcinogen is metabolized by phase I enzymes to a large number of metabolites including phenols, arene oxides, quinones, dihydrodiols, and diol epoxides.
  • An overview of BP metabolic way leading to the formation of (+)-anti-BPDE-dG adduct is presented in FIG. 1 .
  • the ultimate carcinogen (+)-anti-BPDE is formed from BP by two rounds of cytochrome P450-mediated oxidation.
  • the first step of this oxidation leads preferentially to ( ⁇ )-7,8-dihydro-7,8-dihydrobenzo(a)pyrene [( ⁇ )BP-7,8-diol].
  • the diol is further oxidised primarily to the highly mutagenic (+)-r7,t-8-dihydroxy-t-9,10-oxy-7,8,9,10-tetrahydro-BP [(+)-anti-BPDE].
  • ROS from the cigarette smoke may be in part responsible for the increased BPDE-dG adduct formation.
  • My invention provides (i) a means for determining the relative contribution of ROS in cigarette smoke on the activation of BP-7,8-diol in comparison with cytochrome P450; (ii) a means for establishing whether cigarette smoke's ROS promotes the carcinogenic process by contributing to the metabolism of BP-7,8-diol resulting in an increase in the formation of the critical lung BPDE-dG; (iii) a filter containing a scavenger of cigarette free radicals to significantly decrease the formation of BPDE-dG; and (iv) use of said filter to significantly decrease the function of BPDE-dG adducts.
  • Proteinase K (EC 3.4.21.64, from Tritirachium album ) was purchased from Sigma (St. Louis, Mo.), RNase T1 (EC 3.1.21.3, from Aspergillus oryzae ) and RNase (DNase free, heterogeneous mixture of ribonucleases from bovine pancreas) were obtained from Boehringer Mannheim (Mannheim, Germany).
  • Phosphate-buffered saline (PBS) contained 3.0 mM KCl, 1.5 mM KH 2 HPO 4 , 140 mM NaCl, 8.0 mM Na 2 HPO 4 , (pH 7.4), HPLC-grade water, MeO H, ether and ethanol for spectroscopy from E.
  • HPLC High-performance liquid chromatography
  • Cigarette Smoke/PBS Solution (CSS). Smoking was performed according to Pryor et al without the Cambridge filter. Essentially the same smoke collecting method has been used earlier by Nakayama et al. The smoke from burning 8 cm of one cigarette (Marlboro) during 3.8 min with the help of constant vacuum generated from a water pump was bubbled through 10 ml of phosphate-buffered saline (PBS) solution which traps both the gas-phase and tar cigarette smoke chemicals. As there were no water-insoluble tar compounds present on the walls of the wash bottles, a major part of the water-soluble compounds from the smoke of a single cigarette was contained in the 10 ml PBS solution.
  • PBS phosphate-buffered saline
  • CSS cigarette smoke solution
  • the level of the resulting ( ⁇ )-anti BPDE-dG adduct was measured (see below). As control an experiment without CSS was performed.
  • the human mammary carcinoma cell line MCF-7 was grown in 150-cm 2 cell culture flasks in a total volume of 20 ml minimal essential medium E-MEM supplemented with 10% FCS, 15 mM Hepes buffer, and antibiotics (200 units/ml penicillin, 200 ⁇ g/ml streptomycin, and 25 ⁇ g/ml ampicillin). Cells were maintained and treated at 37° C. in 5% CO 2 /95% air atmosphere.
  • DNA Preparation and Hydrolysis DNA isolation from MCF-7 cell pellets was carried out by treatment with RNase, proteinase K, salting procedure (31) and chloroform. Briefly, the cell pellets were resuspended in EDTA-sodium dodecyl sulfate (SDS) buffer [10 mM Tris buffer, 1 mM Na 2 EDTA, 1% SDS (w/v), pH 8] incubated for 1 h at 37° C. with RNase T1 (2000 U/ml) and RNase A (DNase free; 100 ⁇ g/ml) on a shaker (100 rpm). Then proteinase K (300 ⁇ g/ml) was added and the incubation continued overnight at 37° C.
  • SDS EDTA-sodium dodecyl sulfate
  • the portion of DNA to be hydrolyzed was rinsed with 100% ethanol to remove unbound BP-tetrols.
  • the DNA, free of unbound BP-tetrols, was dissolved in water and the DNA concentration was determined by A 260 nm .
  • the purity was ascertained by the ratios at A 260 /A 280 and A 260 /A 230 .
  • the amount of DNA for analysis was hydrolyzed as described previously by incubation at 90° C. for 4 hour in a final concentration of 0.1 N HCl. This releases tetrols ( FIG. 3 ) from BPDE-DNA adducts with >90% recovery.
  • the volume of the hydrolysate for injection was made 700 ⁇ l containing 5-10 ⁇ g DNA.
  • BPDE-N 2 -dG adduct level Determinations of BPDE-N 2 -dG adduct level.
  • the adduct levels were determined by HPLC-FD as previously described [32,33] using r-7,c-9,t-8,t-10-tetrahydroxy-7,8,9,10-tetrahydrobenzo(a)pyrene (BP-tetrol II-1) as an internal standard [34].
  • the hydrolysate was loaded onto a Latex pre-column module (HD-Germany) containing 5 ⁇ m C 18 reverse-phase materiel (Nucleosil 100) equilibrated with 10% MeOH and washed for 20 min with 12 ml 10% MeOH.
  • BP tetrol I-1 trans-anti-BP-tetrol
  • BP-tetrol II-1 trans-syn-BP-tetrol
  • internal standard 36.9 min
  • BP tetrol 11-2 cis-syn-BP-tetrol
  • the detection limit was 0.5 pg of BP tetrol I-1 and BP-tetrol II-1.
  • the level of each BP-tetrol was determined by using a standard curve generated from the fluorescence peak area of authentic BP-tetrol standard analyzed just before the analysis of MCF-7 samples.
  • the BP-tetrol-I-1 detected is derived after hydrolysis of (+)-anti-BPDE-DNA adduct.
  • the hydrolysis of ( ⁇ )-anti-BPDE-dG leads to the formation of BP-tetrol 1-2, which however is unstable and is converted in BP-tetrol I-1 ( FIG. 3 ) (38).
  • the level of the formed ( ⁇ )-anti-BPDE-dG was measured by the quantity of BP-tetrol I-1 found on HPLC runs. Based on the finding that BPDE reacting with DNA produce primarily BPDE-N 2 -dG (7), I assumed that BP-tetrol-I-1 level corresponds to this of BPDE-N 2 -dG.
  • the HPLC runs were quantitatively reproducible, and variability between the two assays was lower than 5%.
  • BP molecular signature The mechanism of mutagenesis by BP is sufficiently well defined and used as a “molecular signature” to establish the causal nature between particular genetic events in development of tumors and carcinogenic exposure (the “smoking gun”).
  • the “BP molecular signature” has major implication for pinpointing the tobacco smoke as the cause of human lung cancer, and for the elaboration of specific strategies to minimize tobacco smoking, or introduce preventive measures.
  • Specific agents used in cancer chemoprevention appear to act by inhibiting carcinogen damage to DNA, mutagenesis, tumor promotion and/or tumor progression.
  • CS is an aerosol of complex chemical composition containing both organic and inorganic compounds, of which 4800 have been identified so far. Both vapor phase and particulate phase of smoke are known to possess free radicals.
  • the radicals in the particulate phase are relatively stable and consist of a hydroquinone, semiquinone, quinone complex
  • this complex is an active redox system capable of reducing molecular oxygen to produce superoxide, eventually leading to hydrogen peroxide and hydroxyl radicals.
  • CS carcinogens at least 60 different CS carcinogens have been implicated in tumor initiation and promotion; the most potent carcinogens agent contained in CS are BP and NNK (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone).
  • the ( ⁇ )-BP-7,8-diol may be metabolized by both pathways and results in the formation of (+)-anti-BPDE, the ultimate form of BP, and ( ⁇ )-syn-BPDE.
  • the different pathways can be distinguished by HPLC analysis since the tetrols derived from anti- and syn-BPDE respectively are clearly separated under my conditions.
  • Cigarette smoke increased linearly and dose dependently the ROS dependent formation of ( ⁇ )-anti-BPDE-dG ( FIG. 4 a ) and decreased the CYPs dependent formation of (+)-syn-BPDE-dG adduct measured by the formation of BP-tetrol II. This decrease is also dose dependant and the inverse of DNA adducts increased linearly with cigarette smoke concentration ( 4 b ).
  • the level of adduct formation at 6 hours was considerably lower than that observed after 12 and 24 hours of exposure.
  • the cells were treated for 12 and 18 hours with BP to induce the formation of ( ⁇ )-BP-7,8 diol which is substrate for ROS.
  • Indirect confirmation for the preferentially formation of ( ⁇ )-BP-7,8-diol is the absence of BP-tetrol II derived from syn-BPDE on HPLC runs which precursor is (+)-BP-7,8-diol ( FIG. 3 ).
  • the cells were then exposed for 2 hours with CSS of cigarette smoke together with BP.
  • the HPLC runs show that there is only one peak on chromatograms which correspond to BP-tetrol I derived from (+)-anti-BPDE-dG.
  • the difference between cells treated with CSS and those non treated (controls) is presented on FIG. 5 .
  • Rosemary Rosmarinus officinalis Labiatae
  • DMBA 7,12-dimethylbenz(a)antracene
  • Rosemary extracts, carnosic acid and carnosol strongly inhibit phase I enzyme, CYP 450 activities and induce the expression of the phase II enzyme, glutathione S-transferase (GST) and quinone reductase activities.
  • Carnosol inhibits nitric oxide (NO) production in activated macrophage.
  • the antioxidant property had been reffered to as the mechanistic basis of their protective effects.
  • the results presented in FIG. 6 were obtained when the MCF-7 cells were treated with BP.
  • Two groups of experiments were performed (A and B). The cells were treated with BP for 12 and 18 hours respectively following with CSS from the two filters for another 2 hours together with BP (Scheme 1).
  • two controls for each group were performed: 12 and 14 hours for group A, 18 and 20 hours for group B.
  • the CSS from the standard filter double the binding level obtained for 14 and 20 hours.
  • rosemary filter strongly impedes the increase obtained by the standard filter, more than 70% in the two groups ( FIG. 6 ).
  • the modified filter scavengers ROS and consequently decreases the activation of ( ⁇ )-BP-7,8-diol ( FIG. 3 ).
  • rosemary powder may have also other mechanisms to reduce BPDE-dG formation.
  • My inventive rosemary cigarette filter therefore is a promising candidate for chemopreventive programs with the aim to reduce BPDE-dG in bronchial epithelial cells.

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Cited By (2)

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WO2017155739A1 (en) * 2016-03-07 2017-09-14 R.J. Reynolds Tobacco Company Rosemary in a tobacco blend
CN113029710A (zh) * 2021-03-15 2021-06-25 中国烟草总公司郑州烟草研究院 一种用于体外毒性测试的加热卷烟全烟气的提取方法

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WO2012136317A1 (de) * 2011-04-04 2012-10-11 Cognis Ip Management Gmbh Rosmarinsäure zur raucherentwöhnung
CN110066863B (zh) * 2019-05-22 2023-01-31 山西医科大学 一种bpde加合基因的鉴定方法

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FR2564296A1 (fr) * 1984-05-16 1985-11-22 Grenet Edouard Filtre pour cigarettes
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JPH07155161A (ja) * 1992-12-26 1995-06-20 Setsuo Kuroki 複合紙巻きたばこ
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WO1999033365A1 (fr) * 1997-12-24 1999-07-08 Biosynthec Utilisation de composes polyphenoliques ou de leurs derives comme capteurs de radicaux libres dans les filtres de cigarette
US20060213533A1 (en) * 1997-12-24 2006-09-28 Imam Emami Use of polyphenol compounds or derivatives thereof as free-radical scavengers in cigarette filters

Cited By (3)

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Publication number Priority date Publication date Assignee Title
WO2017155739A1 (en) * 2016-03-07 2017-09-14 R.J. Reynolds Tobacco Company Rosemary in a tobacco blend
US10226066B2 (en) 2016-03-07 2019-03-12 R.J. Reynolds Tobacco Company Rosemary in a tobacco blend
CN113029710A (zh) * 2021-03-15 2021-06-25 中国烟草总公司郑州烟草研究院 一种用于体外毒性测试的加热卷烟全烟气的提取方法

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