Monohalogenated acetamide-induced cellular stress and genotoxicity are related to electrophilic softness and thiol/thiolate reactivity

Haloacetamides (HAMs) are cytotoxic, genotoxic, and mutagenic by-products of drinking water disinfection. They are soft electrophilic compounds that form covalent bonds with the free thiol/thiolate in cysteine residues through an SN2 reaction mechanism. Toxicity of the monohalogenated HAMs (iodoacetamide, IAM; bromoacetamide, BAM; or chloroacetamide, CAM) varied depending on the halogen substituent. The aim of this research was to investigate how the halogen atom affects the reactivity and toxicological properties of HAMs, measured as induction of oxidative/electrophilic stress response and genotoxicity. Additionally, the authors wanted to determine how well in silico estimates of electrophilic softness matched thiol/thiolate reactivity and in vitro toxicological endpoints. Each of the HAMs significantly induced nuclear Rad51 accumulation and ARE signalling activity compared to a negative control. The rank order of effect was IAM>BAM>CAM for Rad51, and BAM?IAM>CAM for ARE. In general, electrophilic softness and in chemico thiol/thiolate reactivity provided a qualitative indicator of toxicity, as the softer electrophiles IAM and BAM were more thiol/thiolate reactive and were more toxic than CAM.

Authors: Pals JA, Wagner ED, Plewa MJ, Xia M, Attene-Ramos MS. ; Full Source: Journal of Environmental Science (China). 2017 Aug; 58:224-230. doi: 10.1016/j.jes.2017.04.027. Epub 2017 May 9.