Reactivity of hydrazinophthalazine drugs with the lipid peroxidation products acrolein and crotonaldehyde.
The nucleophilic drug hydralazine strongly inhibits cell toxicity mediated by acrolein, a short chain 2-alkenal formed during lipid peroxidation. We here report the chemistry of acrolein-trapping by hydralazine, and show that together with its structural analogue dihydralazine, it also readily traps crotonaldehyde. Isolable reaction products included (1E)-acrylaldehyde phthalazin-1-ylhydrazone (E-APH), (1Z)-acrylaldehyde phthalazin-1-ylhydrazone (Z-APH), (1E,2E)-but-2-enal phthalazin-1-ylhydrazone (E-BPH) and (1Z,2E)-but-2-enal phthalazin-1-ylhydrazone (Z-BPH). Concentration-dependent formation of (1E)-acrylaldehyde phthalazin-1-ylhydrazone was observed in the culture media of cells co-exposed to hydralazine and the acrolein precursor allyl alcohol. These aldehyde-sequestering properties of hydrazinophthalazine drugs may contribute to the protection they provide against 2-alkenal-mediated toxicity.
Kaminskas
Lisa M
LM
Molecular Toxicology Research Group, Department of Clinical and Experimental Pharmacology, University of Adelaide, Adelaide, SA 5005, Australia.
Pyke
Simon M
SM
Burcham
Philip C
PC
D000171:Acrolein / Q000737:chemistry* / Q000633:toxicity; D000447:Aldehydes / Q000737:chemistry* / Q000633:toxicity; D000818:Animals; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D003470:Culture Media; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006830:Hydralazine / Q000737:chemistry* / Q000494:pharmacology; D007700:Kinetics; D015227:Lipid Peroxidation; D051379:Mice; D015394:Molecular Structure
D000447:Aldehydes; D003470:Culture Media; D006830:Hydralazine; D000171:Acrolein; C012796:2-butenal