Caffeine and Other Methylxanthines as Interceptors of Food-Borne Aromatic Mutagens: Inhibition of Trp-P‑1 and Trp-P‑2 Mutagenic Activity

Caffeine is one of the most important biologically active food components. In this article, we demonstrate that caffeine and other methylxanthines significantly reduce the mutagenic activity of two food-derived heterocyclic aromatic amines, Trp-P-1 and Trp-P-2 in the <i>Salmonella typhimurium</i> TA98 strain. Moreover, protection against Trp-P-1-induced mutagenicity was independent of liver S9 enzymatic fraction, suggesting that mechanisms other than modulation of mutagen bioactivation can contribute to the observed protective effects. UV–vis spectroscopy and computational studies revealed that methylxanthines intercept Trp-P-1 and Trp-P-2 in noncovalent molecular complexes, with association constants (<i>K</i>_AC) in the 10² M^–1 range. Enthalpy values (Δ<i>H</i> about −30 kJ·mol^–1) of mutagen–methylxanthine heterocomplexation obtained microcalorimetrically correspond to stacking (π–π) interactions. Finally, we demonstrated that the biological activity of Trp-P-1 and Trp-P-2 is strictly dependent on the presence of the mutagen in a free (unbound with methylxanthine) form, suggesting that mutagen sequestration in stacking heterocomplexes with methylxanthines can decrease its bioavailability and diminish its biological effects