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Paracetamol catalyzes myeloperoxidase-initiated lipid oxidation in LDL
S Kapiotis1, G Sengoelge, M Hermann
1Clinical Institute of Medical and Chemical Laboratory Diagnostics, University of Vienna, Austria.
Abstract:
The oxidative modification of LDL may play a significant role in atherogenesis. Myeloperoxidase (MPO) expressed in human atherosclerotic plaques has been suggested to be operative in vivo, making LDL atherogenic. Tyrosyl radicals generated by MPO have been shown to act as physiological pro-oxidants of lipid peroxidation in LDL. Assuming that a variety of phenolic compounds are able to form phenoxyl radicals when exposed to peroxidases, we tested the ability of paracetamol, a known analgesic drug with a tyrosine-like monophenolic structure, to act as a pro-oxidant of lipid peroxidation in LDL. Spectroscopic analyses indicated that paracetamol, similar to tyrosine, could undergo peroxidase-induced phenoxyl radical formation, which was inhibited by the radical scavenger ascorbic acid as well as by heme poisons and catalase. Measurement of conjugated dienes and lipid hydroperoxides in LDL preparations exposed to MPO/H2O2 in the absence or presence of paracetamol revealed that the drug could act as a catalyst of lipid oxidation in LDL. Similar results were found when LDL oxidation was performed with activated human neutrophils, which use MPO to promote lipid peroxidation. In conclusion, the results suggest that paracetamol could act, via a phenoxyl radical, as a catalyst of LDL oxidative modification by MPO.
Insights
Paracetamol can accelerate LDL oxidation by myeloperoxidase (MPO), potentially contributing to atherosclerosis. This occurs via MPO-induced phenoxyl radical formation, similar to tyrosine.
Area of Science:
- Biochemistry
- Cardiovascular Research
- Pharmacology
Background:
- Oxidative modification of low-density lipoprotein (LDL) is a key factor in atherogenesis.
- Myeloperoxidase (MPO), an enzyme found in atherosclerotic plaques, is implicated in making LDL atherogenic.
- MPO generates tyrosyl radicals that promote lipid peroxidation in LDL.
Purpose of the Study:
- To investigate if paracetamol, a phenolic compound, can act as a pro-oxidant in LDL lipid peroxidation.
- To explore the mechanism of paracetamol's potential pro-oxidant activity in LDL.
Main Methods:
- Spectroscopic analysis to detect paracetamol's phenoxyl radical formation.
- Measurement of conjugated dienes and lipid hydroperoxides in LDL.
- LDL oxidation assays using MPO/H2O2 and activated human neutrophils.
Main Results:
- Paracetamol formed phenoxyl radicals upon peroxidase induction, similar to tyrosine.
- Paracetamol catalyzed lipid peroxidation in LDL, evidenced by increased conjugated dienes and lipid hydroperoxides.
- Radical scavenging and inhibition studies confirmed the involvement of radical formation and MPO activity.
Conclusions:
- Paracetamol can act as a catalyst for LDL oxidative modification mediated by MPO.
- The pro-oxidant activity of paracetamol involves MPO-induced phenoxyl radical formation.
- These findings suggest a potential mechanism linking paracetamol use to MPO-driven atherogenesis.