# The Effects of Salicyluric Acid, the Main Metabolite of Aspirin, on Lipid Peroxidation Induced by Iron and Copper Ions in a Lipid Membrane Model

## TL;DR

This study investigates how salicyluric acid, a metabolite of aspirin, interacts with iron and copper in lipid membranes, finding it does not promote harmful oxidation reactions.

## Contribution

The study reveals SUA's localization in lipid membranes and its lack of pro-oxidant activity, offering new insights into its role in iron metabolism and toxicity.

## Key findings

- SUA does not promote iron- or copper-induced lipid peroxidation in model membranes.
- SUA incorporates into lipid bilayers, stabilizing ligands and reducing metal chelation.
- SUA localizes shallowly in membranes, interacting mainly with lipid head groups and acyl chains.

## Abstract

Salicyluric acid (SUA), the main metabolite of aspirin and a natural product, is known for its ability to chelate iron and other metal ions. In particular, the chelation and increased excretion of iron by SUA may contribute to the aspirin-induced iron deficiency anemia observed in long-term aspirin users. The redox activity of iron and copper complexes of drugs and also drug metabolites, such as SUA, is an important parameter of their overall toxicity profile, including the induction of ferroptosis, which has been associated with many diseases. In this context, the effect of SUA on iron- and copper-induced lipid peroxidation and also its localization within a model lipid membrane have been investigated. A combination of physicochemical methods, including Nuclear Magnetic Resonance (1H NMR), molecular dynamics (MD), and Nuclear Overhauser Effect Spectroscopy (1H NOESY), has been used to demonstrate that SUA does not promote the peroxidation of linoleic acid micelles in the presence of Fe(II) or Cu(II) ions. NMR experiments revealed that SUA incorporates into the lipid bilayer, which stabilizes the ligands and inhibits its metal chelation ability in comparison to the control. NOESY experiments and MD simulations further showed that SUA localizes shallowly within the membrane, interacting primarily with the head group and upper acyl chain regions of lipids. These findings provide crucial insights into the membrane redox reactivity and other behavior of SUA, explaining its lack of pro-oxidant activity and also highlighting its complex role in the pharmacological and toxicological effects on iron metabolism in long-term aspirin users.