Cytotoxicity of Halogenated Tyrosyl Compounds, an Emerging Class of Disinfection Byproducts

Abstract

Halogenated amino acids and peptides are an emerging class of disinfection byproducts (DBPs), having been detected in drinking water and in washed food products. However, the toxicological significance of these emerging DBPs remains unclear. In this study, the cytotoxicity of eight halogenated tyrosyl compounds was investigated in Chinese hamster ovary (CHO) cells using real-time cell analysis (RTCA). Dihalogenated tyrosyl compounds are more cytotoxic than their monohalogenated analogues. The cytotoxicity of the dihalogenated compounds is associated with their ability to induce intracellular reactive oxygen species (ROS), suggesting that oxidative stress is an important toxicity pathway of these compounds. Pearson correlation analysis of the cytotoxicity (IC50 values) of these compounds with eight physicochemical parameters showed strong associations with their lipophilicity (logP) and reactivity (polarizability, E LUMO). Finally, cytotoxicity testing of the concentrated extracts of a chloraminated mixture of eight dipeptides with bromide or iodide showed the cytotoxicity of these mixtures in the order: iodinated peptides > brominated peptides ≥ chlorinated peptides. These results demonstrate that halogenated peptide DBPs are toxicologically relevant, and further research is needed to understand the implications of long-term exposure for human health.

Natural and Synthetic Halogenated Amino Acids—Structural and Bioactive Features in Antimicrobial Peptides and Peptidomimetics

“…The compounds ( 1 ) and ( 3 )– )10 ) were found to be variously bioactive as antibacterial, anticancer, antiparasitic, antiplasmodial, antiinflammatory, and antifouling molecules [ 59 , 60 , 61 , 62 , 63 , 64 ]. A recent study focused on identifying novel marine halogenated tyrosines, identified them as components of valviamides A−D ( 11 – 14 in Table 2 ) from the cnidarians Antipathozoanthus hickmani and Parazoanthus darwini ( Table 2 ).…”

“…It should be noted that free halogenated amino acids and halogenated peptides are increasingly found in drinking water and in washed foods [ 64 ]. These compounds cannot properly be considered to be native, although they are found dispersed in nature.…”

“…In fact, they are formed in the environment by reaction of amino acids and peptides with disinfectants (which contain electrophilic bromine and chlorine), following a mechanism similar to that of biosynthesis. Therefore, halogenated peptides and amino acids are a class of emerging disinfection by-products (DBPs), whose toxicity and potential bioactivity are only now coming to light [ 64 ]. In this pioneering study, tyrosines were shown to be the preferred site of halogenation of peptides leading to the formation of the compounds ( 1 ) and ( 3 )–( 10 ).…”

Formation Mechanism of Iodinated Aromatic Disinfection Byproducts: Acid Catalysis with H2OI+

“…13−16 However, aromatic I-DBPs show 50−200 times higher developmental toxicity and growth inhibition than aliphatic I-DBPs 11,17 and other known I-DBPs. 10,18 Using the precursor ion scan method, numerous aromatic I-DBPs have been detected in chloraminated waters, tap water, and cooking water. 8,9,11,18,19 For instance, aromatic I-DBPs (e.g., 2,4,6-triiodophenol and 2,6-diiodo-4-nitrophenol) were widely detected in finished drinking water samples from China with concentrations up to 31 ng L −1 .…”

Formation and Cytotoxicity of Halophenylacetamides: A New Group of Nitrogenous Aromatic Halogenated Disinfection Byproducts in Drinking Water

“…Fourth, with regard to isomers, 3-CPAcAm showed a relatively higher cytotoxicity than 2-CPAcAm; similar in the case for 3-BPAcAm in comparison to 2-BPAcAm, implying that the isomeric position might play a considerable role in affecting the cytotoxicity of HPAcAms. Thereafter, to compare with other nitrogenous aromatic halogenated DBPs, the cytotoxicity index (CTI) for HPAcAms as well as halonitrophenols, halogenated tyrosyl dipeptides, halophenylacetonitriles, and halopyrroles was determined by calculating the reciprocal of the median EC 50 value of all individual members of a single DBP category . As shown in Supporting Information Table S9, HPAcAms showed higher cytotoxicity than halogenated tyrosyl dipeptides and lower cytotoxicity than halonitrophenols, halophenylacetonitriles, and halopyrroles (it is worth noting that there is a certain difference in the cytotoxicity test methods adopted in these previous studies).…”