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 (A1DH) isozyme. The involvement of cytochrome P-450 in vivo was shown indirectly by (a) the ability of SKF-525A to block pargylineinduced acetaldehydemia, (b) the prolongation of phenobarbital sleeping time by pargyline, and (c) the enhancement of pargylineinduced 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 A1DH 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.
KeywordsAlDH Activity Propargyl Alcohol Microsomal System Aldehyde Dehydrogenase Activity Carbinol Amine
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