Microsomal N-depropargylation of pargyline to propiolaldehyde, an irreversible inhibitor of mitochondrial aldehyde dehydrogenase.

Rat liver microsomes catalyzed the conversion of pargyline (N-methyl-N-propargylbenzylamine) to propiolaldehyde, a potent inhibitor of the low Km mitochondrial aldehyde dehydrogenase (AlDH) isozyme. The involvement of cytochrome P-450 in vivo was shown indirectly by (a) the ability of SKF-525A to block pargyline-induced acetaldehydemia, (b) the prolongation of phenobarbital sleeping time by pargyline, and (c) the enhancement of pargyline-induced acetaldehydemia by phenobarbital pretreatment. Propiolaldehyde was isolated as its semicarbazone by incubating pargyline with either phenobarbital-induced or uninduced rat liver microsomes and an NADPH-generating system, the latter being required for propiolaldehyde formation. In vitro studies with liver mitochondria showed that propiolaldehyde inhibition of AlDH was temperature- and time-dependent and irreversible. We propose that the cytochrome P-450 catalyzed conversion of pargyline to its active metabolite, propiolaldehyde, proceeds via a mechanism involving N-depropargylation, viz., hydroxylation of pargyline alpha to the acetylenic bond forming a carbinolamine intermediate, followed by dissociation.