Application of structure–activity relationships to investigate the molecular mechanisms of hepatocyte toxicity and electrophilic reactivity of α,β-unsaturated aldehydes

✍ Scribed by Katie Chan; Raymond Poon; Peter J. O'Brien

• Publisher: John Wiley and Sons
• Year: 2008
• Tongue: English
• Weight: 405 KB
• Volume: 28
• Category: Article
• ISSN: 0260-437X
• DOI: 10.1002/jat.1369

✦ Synopsis

Abstract

Covalent binding of reactive electrophiles to cellular targets is a molecular interaction that has the potential to initiate severe adverse biological effects. Therefore, a measure for electrophilic reactivity with biological nucleophiles could serve as an important correlate to toxic effects such as hepatocyte death. To determine if electrophile reactivity correlates with rat hepatocyte cytotoxicity, the inherently electrophilic α,β‐unsaturated aldehydes were chosen for investigation. Reactivity was measured with simple assays that used glutathione, a soft nucleophile, and butylamine, a harder nucleophile, as models for protein thiol and amine nucleophilic sites, respectively. Despite their higher reactivity with thiols, a linear relationship was only observed between hepatocyte cytotoxicity and amine reactivity. Structure–activity relationships were also investigated for hepatocyte toxicity, and results showed toxicity was well modelled by log P and electronic parameters E~LUMO~ and partial charge of the carbonyl carbon (
). Hydrophobicity and electronic descriptors were only significant in separate distinct models, suggesting that there were simultaneously occurring mechanisms that affected toxicity. Log P was linked to the ease of oxidation by a microsomal aldehyde dehydrogenase enzyme, while the electronic descriptors and amine reactivity were linked to direct alkylation. Even with the presence of electrophile characteristics, α,β‐unsaturated aldehyde hepatocyte toxicity could not be predicted exclusively by electrophilic reactivity as oxidative metabolism was also a factor for toxicity. Copyright © 2008 John Wiley & Sons, Ltd.