Metabolic depropargylation and its relationship to aldehyde dehydrogenase inhibition in vivo.
The relationship between metabolic depropargylation in vitro to inhibition of the low Km aldehyde dehydrogenase (AIDH) of rat liver mitochondria in vivo was determined for a number of compounds bearing a propargyl substituent on nitrogen or oxygen. Only those compounds which enzymatically released the highly reactive alpha, beta-acetylenic aldehyde, propioladehyde, when incubated in vitro with phenobarbital-induced rat liver microsomes, e.g., tripropargylamine (4), pargyline (1a), and N-propargylbenzylamine (1b), significantly elevated blood acetaldehyde levels when administered in vivo. Mitochondrial AIDH activity in these animals was corresponding reduced to less than or equal to 20% that of control animals. Compounds that did not inhibit mitochondrial AlDH activity to this degree did not produce significant levels of propiolaldehyde when incubated with microsomes. Thus, for this series of compounds, metabolic depropargylation is a requirement for AlDH inhibitory activity in vivo.
D000079:Acetaldehyde / Q000097:blood; D000445:Aldehyde Oxidoreductases / Q000037:antagonists & inhibitors*; D000447:Aldehydes / Q000378:metabolism; D000480:Alkynes / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D008930:Mitochondria, Liver / Q000201:enzymology; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats
D000447:Aldehydes; D000480:Alkynes; C018132:propiolaldehyde; D000445:Aldehyde Oxidoreductases; D000079:Acetaldehyde; D010634:Phenobarbital