Aldehyde-sequestering drugs: tools for studying protein damage by lipid peroxidation products.
Elevated levels of reactive alpha,beta-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.
Burcham
Philip C
PC
Molecular Toxicology Research Group, Department of Clinical and Experimental Pharmacology, Adelaide University, Adelaide, SA 5005, Australia. philip.burcham@adelaide.edu.au
Kaminskas
Lisa M
LM
Fontaine
Frank R
FR
Petersen
Dennis R
DR
Pyke
Simon M
SM
D000171:Acrolein / Q000378:metabolism; D000447:Aldehydes / Q000378:metabolism*; D000818:Animals; D002336:Carnosine / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology; D006801:Humans; D006830:Hydralazine / Q000494:pharmacology; D015227:Lipid Peroxidation / Q000187:drug effects*; D010084:Oxidation-Reduction; D011506:Proteins / Q000737:chemistry*; D011733:Pyridoxamine / Q000494:pharmacology
D000447:Aldehydes; D006146:Guanidines; D011506:Proteins; D006830:Hydralazine; D011733:Pyridoxamine; D000171:Acrolein; D002336:Carnosine; C004479:pimagedine