Role of propiolaldehyde and other metabolites in the pargyline inhibition of rat liver aldehyde dehydrogenase

Abstract

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 dehy drogenase (A1DH). 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 μ;mole/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 CoCl 2 pretreatment of rats partially blocked the pargyline-induced rise in blood acetaldehyde after ethanol. Inhibition of the low K m liver mitochondrial A1DH by propiolaldehyde in vitro exhibited firstorder kinetics, which is consistent with irreversible inhibition. Acetaldehyde did not attenuate the inhibition of A1DH by propiolaldehyde in vitro or by pargyline in vivo. Propargyl alcohol, a substance which is metabolized to propiolaldehyde by alcohol dehydrogenase, also inhibited A1DH in vivo and caused a quantitatively similar rise in blood acetaldehyde after ethanol as pargyline. Other putative metabolites of pargyline, namely benzylamine and propargy lamine, inhibited A1DH in vivo, albeit to a lesser degree than pargyline, but neither of these amines inhibited A1DH 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 A1DH in vivo; however, certain amine metabolites may have contributed to a lesser degree by conversion to yet unknown inhibitory forms.