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: 2.15). 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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    • "Next, 67 μl of solution containing 0.1 μmol of histidine and 0.1 μmol of biotin was added to the mixture, which was then plated on the agar plate with minimal glucose medium, as previously described (Woziwodzka et al. 2013). For the assays conducted without metabolic activation, a previously reported procedure was used (Golunski et al. 2013; Woziwodzka et al. 2011). A mixture containing 50 μl of the overnight culture (cultivated for 4 h at room temperature and then for 12 h at 37 °C with shaking), 60 μl of 3 % NaCl, and 150 μl of the tested chemical was incubated with shaking for 4 h at 37 °C. "
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    ABSTRACT: Bacterial cell envelope is generally accepted as the primary target for a photo-induced oxidative stress. It is plausible that DNA damage occurs during the antimicrobial photoinactivation. Here we investigate the correlation between DNA damage and photoinactivation by evaluating the level of RecA-based DNA repair system in Staphylococcus aureus. By using exogenous photosensitizers (new methylene blue (NMB), toluidine blue O (TBO), 5,10,15,20-tetrakis(1-methyl-4-pyridinio)porphyrin tetra(p-toluenesulfonate) (TMPyP), zinc phthalocyanine (ZnPc), Rose Bengal (RB)) and ALA-induced endogenous porphyrin-dependent blue light (405 nm), several outcomes were observed: (i) an increase of DNA damage (from gel electrophoresis in DNA damage assay), (ii) an increase of recA expression (luminescence assay in recA-lux strain), and (iii) an increase of RecA protein level (Western blotting). When recA expression was repressed by novobiocin, or abolished by deleting the gene, S. aureus susceptibility towards photoinactivation was increased at approximately a hundred-fold. The absence of RecA increases DNA damage to yield bactericidal effect. In novobiocin-resistant mutant (gyrB), as opposed to wild type, neither RecA protein level nor cell's susceptibility was affected by photoinactivation (when novobiocin is present). This is to suggest that GyrB-dependent inhibition mediated recA repression. Therefore, we have established the role of RecA in DNA damage during photoinactivation. With the use of rifampicin mutation frequency and Ames tests, we demonstrated that photoinactivation did not increase S. aureus mutagenesis and potentially is not mutagenic toward eukaryotic cells. The results suggest that the treatment is considered safe. In conclusion, we provide an evidence that recA inhibitor may serve as therapeutic adjuvant for antimicrobial photoinactivation. Clinical relevance of our findings warrants further investigations.
    Applied Microbiology and Biotechnology 08/2015; DOI:10.1007/s00253-015-6863-z · 3.34 Impact Factor
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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 · 2.12 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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    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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