Structure-activity relationships for hepatocyte toxicity and electrophilic reactivity of alpha,beta-unsaturated esters, acrylates and methacrylates.
Covalent binding of reactive electrophiles to cellular targets is a molecular interaction that has the potential to initiate severe adverse biological effects. Therefore, electrophile reactivity towards biological nucleophiles could serve as an important correlate for toxic effects such as hepatocyte death. To determine if reactivity correlates with rat hepatotoxicity, alpha,beta-unsaturated esters, consisting of acrylates and methacrylates, that are inherently electrophilic and exhibit widely varying degrees of reactivity were investigated. Reactivity was measured using simple assays with glutathione and butylamine as surrogates for soft thiol and hard amino biological nucleophile targets. A linear relationship was observed between hepatotoxicity and thiol reactivity only, while no amine reactivity was observed. Structure-activity relationships were also investigated, with results showing toxicity was well modeled by electronic parameters E(LUMO) and partial charge of the carbon atoms in the reactive center. No relationship was observed between toxicity and logP. These results suggest that differences in hepatocyte toxicity of acrylates and methacrylates can be related to their electrophilic reactivity which corresponds to their ability to deplete GSH and protein thiols.
Chan
Katie
K
University of Toronto, Faculty of Pharmacy, Toronto, ON, Canada. katieseekay.chan@utoronto.ca
O'Brien
Peter J
PJ
D000179:Acrylates / Q000737:chemistry / Q000633:toxicity*; D000818:Animals; D002082:Butylamines / Q000737:chemistry; D002627:Chemistry, Physical; D004952:Esters / Q000737:chemistry / Q000633:toxicity*; D005978:Glutathione / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000473:pathology* / Q000648:ultrastructure; D008297:Male; D008689:Methacrylates / Q000737:chemistry / Q000633:toxicity*; D008958:Models, Molecular; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D017207:Rats, Sprague-Dawley; D012044:Regression Analysis; D012995:Solubility; D013329:Structure-Activity Relationship; D013778:Tetrazolium Salts; D013844:Thiazoles
D000179:Acrylates; D002082:Butylamines; D004952:Esters; D008689:Methacrylates; D013778:Tetrazolium Salts; D013844:Thiazoles; C022616:thiazolyl blue; D005978:Glutathione