Aldehyde-sequestering drugs: tools for studying protein damage by lipid peroxidation products

Elevated levels of reactive α,β-unsaturated aldehydes (e.g. malondialdehyde, 4-hydroxynonenal and acrolein) in the affected tissues of various degenerative conditions suggest these substances are active propagators of the disease process. One experimental approach to attenuating damage by these inte...

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Bibliographic Details
Published in:Toxicology (Amsterdam) 2002-12, Vol.181, p.229-236
Main Authors: Burcham, Philip C., Kaminskas, Lisa M., Fontaine, Frank R., Petersen, Dennis R., Pyke, Simon M.
Format: Article
Language:English
Subjects:
4-Hydroxynonenal
Acrolein
Acrolein - metabolism
Aldehydes - metabolism
Animals
Biological and medical sciences
Carnosine - pharmacology
Cell metabolism, cell oxidation
Cell physiology
Dihydralazine
Fundamental and applied biological sciences. Psychology
Guanidines - pharmacology
Humans
Hydralazine
Hydralazine - pharmacology
Lipid peroxidation
Lipid Peroxidation - drug effects
Malondialdehyde
Molecular and cellular biology
Oxidation-Reduction
Proteins - chemistry
Pyridoxamine - pharmacology
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Summary:Elevated levels of reactive α,β-unsaturated aldehydes (e.g. malondialdehyde, 4-hydroxynonenal and acrolein) in the affected tissues of various degenerative conditions suggest these substances are active propagators of the disease process. One experimental approach to attenuating damage by these intermediates employs ‘aldehyde-sequestering drugs’ as sacrificial nucleophiles, thereby sparing cell macromolecules and perhaps slowing disease progression. Drugs with demonstrated trapping activity toward lipid-derived aldehydes include various amine compounds such as aminoguanidine, carnosine and pyridoxamine. We have focused on identifying scavengers of acrolein, perhaps the most toxic aldehyde formed during lipid peroxidation cascades. Various phthalazine compounds (hydralazine and dihydralazine) were found to trap acrolein readily, forming hydrazone derivatives in a rapid Schiff-type reaction. These compounds strongly protect against acrolein-mediated toxicity in isolated hepatocytes.
ISSN:0300-483X
1879-3185
DOI:10.1016/S0300-483X(02)00287-1