Unraveling the Role of Drug-Lipid Interactions in NSAIDs-Induced Cardiotoxicity.

Catarina Pereira-Leite,Kinga Burdach,Marina Figueiredo,Cláudia Nunes,Salette Reis

doi:10.3390/membranes11010024

Catarina Pereira-Leite, Kinga Burdach + Show 3 more

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https://doi.org/10.3390/membranes11010024

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Journal: Membranes	Publication Date: Dec 29, 2020
Citations: 17	License type: CC BY 4.0

Affiliation: University of Porto, Rede de Química e Tecnologia

Abstract

Cardiovascular (CV) toxicity is nowadays recognized as a class effect of non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs). However, their mechanisms of cardiotoxicity are not yet well understood, since different compounds with similar action mechanisms exhibit distinct cardiotoxicity. For instance, diclofenac (DIC) is among the most cardiotoxic compounds, while naproxen (NAP) is associated with low CV risk. In this sense, this study aimed to unravel the role of drug-lipid interactions in NSAIDs-induced cardiotoxicity. For that, DIC and NAP interactions with lipid bilayers as model systems of cell and mitochondrial membranes were characterized by derivative spectrophotometry, fluorometric leakage assays, and synchrotron X-ray scattering. Both DIC and NAP were found to have the ability to permeabilize the membrane models, as well as to alter the bilayers’ structure. The NSAIDs-induced modifications were dependent on the lipid composition of the membrane model, the three-dimensional structure of the drug, as well as the drug:lipid molar ratio tested. Altogether, this work supports the hypothesis that NSAIDs-lipid interactions, in particular at the mitochondrial level, may be another key step among the mechanisms underlying NSAIDs-induced cardiotoxicity.

Highlights

Therapy with nonsteroidal anti-inflammatory drugs (NSAIDs) has been associated with a high incidence of adverse effects, if used in long-term treatments [1].In 1938, Douthwaite and Lintott demonstrated that aspirin induces gastric damage [2], and later, the gastrointestinal (GI) toxicity was identified as a class effect of NSAIDs.The toxicity mechanisms of NSAIDs comprise their systemic effect of reducing the biosynthesis of gastroprotective prostaglandins, and the topical actions of these drugs in the GI tract [3]
The partition coefficient of DIC and NAP were determined at 37 ◦ C and pH 7.4 by derivative spectrophotometry using POPC, POPC:Cholesterol from ovine wool (CHOL) (80:20), POPC:TMCL (85:15), and POPC:PI (85:15) Large unilamellar vesicles (LUVs)
Data analysis performed for DIC to evaluate the partition coefficient in POPC:CHOL (80:20) LUVs is illustrated in Figure 2, as an example

Summary

Introduction

In 1938, Douthwaite and Lintott demonstrated that aspirin induces gastric damage [2], and later, the gastrointestinal (GI) toxicity was identified as a class effect of NSAIDs. The toxicity mechanisms of NSAIDs comprise their systemic effect of reducing the biosynthesis of gastroprotective prostaglandins, and the topical actions of these drugs in the GI tract [3]. The toxicity mechanisms of NSAIDs comprise their systemic effect of reducing the biosynthesis of gastroprotective prostaglandins, and the topical actions of these drugs in the GI tract [3] Among the latter actions, the NSAIDs-lipid interactions were found to be a key factor favoring the occurrence of adverse effects, with numerous contributions from our research group and others [4,5,6,7,8]. The evidence that cyclooxygenase-2 selective inhibitors were related to the occurrence of thrombotic events [10] raised questions about the CV safety of the entire class of NSAIDs

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