Caffeine, pentoxifylline and theophylline form stacking complexes with IQ-type heterocyclic aromatic amines

Department of Molecular and Cellular Biology, Intercollegiate Faculty of Biotechnology UG and MUG, Kładki 24, Gdańsk, Poland.
Bioorganic Chemistry (Impact Factor: 2.14). 02/2011; 39(1):10-7. DOI: 10.1016/j.bioorg.2010.11.001
Source: PubMed

ABSTRACT Methylxanthines (MTX), in particular caffeine (CAF), are known as the most widely consumed alkaloids worldwide. Many accumulated statistical data indicate the protective effect of CAF intake against several types of cancer. One of the possible explanations of this phenomenon is direct non-covalent interaction between CAF and aromatic mutagen/carcinogen molecules through stacking (π-π) complexes formation. Here we demonstrate that CAF and other MTX, pentoxifylline (PTX) and theophylline (TH), form stacking complexes with carcinogenic imidazoquinoline-type (IQ-type) food-borne heterocyclic aromatic amines (HCAs). We estimated neighborhood association constants (K(AC) of the order of magnitude of 10(2)M(-1)) in neutral and acidic environment and enthalpy changes (ΔH values between -15.1 and -39.8kJ/mol) for these interactions using UV-Vis spectroscopy, calculations based on thermodynamical model of mixed aggregation and titration microcalorimetry. Moreover, using Ames test with Salmonella typhimurium TA98 strain and recently developed mutagenicity assay based on bioluminescence of Vibrio harveyi A16 strain, we demonstrated a statistically significant reduction in HCAs mutagenic activity in the presence of MTX.

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    • "Fig. 2 contains the biological data recalculated into A D units according to Eq. (1), and the A D (y 0 ) dependence computed from Eqs. (2) and (3) under the sole action of the interceptor mechanism (i.e. K YN ¼0) (the magnitudes of the complexation parameters were taken from Woziwodzka et al. (2011) and the estimated magnitude of the IQ- DNA binding was taken as K XN ¼2970 M À 1 from Sartorius and Schneider (1997)). Small variation of the binding parameters within 10% range enabled to achieve very good fitting of experimental data (solid line in Fig. 2) suggesting that the IQ- CAF systems follow the interceptor mechanism in the same way as the IQ-CHL systems discussed above. "
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    ABSTRACT: According to the theory of interceptor-protector action a quantitative link between the physico-chemical parameters of molecular complexation and in vitro biological effect in aromatic drug-interceptor systems must exist. In the present communication such link between relative change in mutagenicity of IQ-type aromatic mutagens on addition of aromatic interceptor molecules with equilibrium hetero-association constants of mutagen-interceptor complexation has been found using the published in vitro data in bacteria cell systems.
    Journal of Theoretical Biology 06/2014; 357. DOI:10.1016/j.jtbi.2014.06.016 · 2.30 Impact Factor
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    • "However, the continuous introduction of caffeine may cause subtle effects acting as a pseudo-persistent pollutant for its continuous release in the environment and little is known about its chronic effects (OECD, 2002). Furthermore, several studies reported the genotoxic potential and mutagenic potential of caffeine on animal models and results are inconsistent and inconclusive (Choundhury and Palo, 2004) even if caffeine showed antigenotoxic activity towards known genotoxins (Woziwodzka et al., 2011). "
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    ABSTRACT: Caffeine is ubiquitous in surface and ground waters and it has been proposed as a marker of the anthropogenic pressure on the environment. Sewage treatment plants based on active sludges seem to be not very efficient in its complete removal from effluents while additional disinfection treatments by chlorination are able to do it. In a simulation of the chlorination step herein we report that caffeine is transformed in six by-products: 8-chlorocaffeine, 1,3-dimethyl-5-azabarbituric acid, N,N'-dimethylparabanic acid, N,N'-dimethyloxalamide, N-methylurea and N,N'-dimethylurea. The ecotoxicity of caffeine and identified compounds was evaluated on the rotifer Brachionus calyciflorus and the alga Pseudokirchneriella subcapitata to assess acute and chronic toxicity, while SOS Chromotest and Ames Test were used to detect the genotoxic potential of the investigated compounds. Moreover, we assessed the possible antigenotoxic effect of the selected compounds using SOS Chromotest after co-incubation with the standard genotoxin, 4-nitroquinoline 1-oxide. Chronic exposure to these compounds caused inhibition of growth population on the rotifer while the algae seemed to be unaffected. Results indicated that caffeine (1), N,N'-dimethyloxamide (4) and N,N'-dimethylparabanic acid (5) reduced β-galactosidase activity in comparison with positive control, both at 1 and 5mg/L of 4-NQNO with a good dose-response.
    Science of The Total Environment 10/2013; 470-471C:453-458. DOI:10.1016/j.scitotenv.2013.10.005 · 4.10 Impact Factor
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    • "This mechanism of protection is known as " interceptor " mode of CAF and other methylxanthines action and was proposed by Bedner et al. [19]. The " interceptor " mode of CAF was described and analyzed for HCAs [15] and several other aromatic compounds: ethidium bromide [20] [21], propidium iodide [19] [20], quinacrine mustard, ICR170, ICR191 [22], proflavine [23], and several anticancer drugs [17] [24] [25]. Similar mechanism was also described for interaction of chlorophyllin (CHL) [26] and other natural constituents of human diet [27] with several aromatic compounds. "
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    ABSTRACT: Food-borne heterocyclic aromatic amines (HCAs) are known mutagens and carcinogens present especially in Western population diet, which contains large amount of meat and its products. HCAs are capable of interacting with DNA directly through the formation of covalent adducts, however this process requires biological activation in liver, mainly by cytochrome P450 enzymes. This process may produce mutations and in consequence may contribute to the development of cancer. However, there are many studies showing that several biologically active aromatic compounds (BACs) may protect against genotoxic effects of HCAs. Direct interactions and noncovalent heterocomplexes formation may be one of the most important mechanisms of such protection. This work describes several BACs present in human diet, which are capable of molecular complexes formation with HCAs and protect cells as well as whole organisms against HCAs action.
    03/2013; vol. 2013, Article ID 740821. DOI:10.1155/2013/740821
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