Role of propiolaldehyde and other metabolites in the pargyline inhibition of rat liver aldehyde dehydrogenase.
The metabolism of pargyline proceeds by way of three separate cytochrome P-450 catalyzed N-dealkylation reactions: N-depropargylation, N-demethylation and N-debenzylation. Propiolaldehyde, a product of N-depropargylation, is a potent inhibitor of aldehyde dehydrogenase (AlDH). The formation of pargyline-derived propiolaldehyde by isolated rat liver microsomes in vitro was confirmed using gas chromatographic/mass spectrometric techniques. The measured rates of propiolaldehyde formation for uninduced and phenobarbital-induced microsomes in vitro were 0.2 +/- 0.03 and 0.9 +/- 0.2 mumole/30 min/g wet weight liver respectively. However, these rates may have been artificially low due to competition between semicarbazide, the trapping agent, and microsomal proteins for the generated propiolaldehyde. CO significantly inhibited the microsome-catalyzed N-depropargylation reaction in vitro, whereas CoCl2 pretreatment of rats partially blocked the pargyline-induced rise in blood acetaldehyde after ethanol. Inhibition of the low Km liver mitochondrial AlDH by propiolaldehyde in vitro exhibited first-order kinetics, which is consistent with irreversible inhibition. Acetaldehyde did not attenuate the inhibition of AlDH by propiolaldehyde in vitro or by pargyline in vivo. Propargyl alcohol, a substance which is metabolized to propiolaldehyde by alcohol dehydrogenase, also inhibited AlDH in vivo and caused a quantitatively similar rise in blood acetaldehyde after ethanol as pargyline. Other putative metabolites of pargyline, namely benzylamine and propargylamine, inhibited AlDH in vivo, albeit to a lesser degree than pargyline, but neither of these amines inhibited AlDH directly. Monoamine oxidase was implicated in the conversion of benzylamine to an active inhibitory species, possibly an imine. From these studies, we conclude that propiolaldehyde was the primary metabolite responsible for the pargyline inhibition of AlDH in vivo; however, certain amine metabolites may have contributed to a lesser degree by conversion to yet unknown inhibitory forms.
DeMaster
E G
EG
Shirota
F N
FN
Nagasawa
H T
HT
D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors*; D000447:Aldehydes / Q000378:metabolism*; D000818:Animals; D002248:Carbon Monoxide / Q000494:pharmacology; D003035:Cobalt / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology; D006863:Hydrogen-Ion Concentration; D006900:Hydroxylation; D008099:Liver / Q000201:enzymology*; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D008930:Mitochondria, Liver / Q000201:enzymology; D010293:Pargyline / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors
D000447:Aldehydes; D003035:Cobalt; C018132:propiolaldehyde; D002248:Carbon Monoxide; D003577:Cytochrome P-450 Enzyme System; D010293:Pargyline; D000444:Aldehyde Dehydrogenase; C018021:cobaltous chloride