DAIDZIN AND ITS ANTIDIPSOTROPIC ANALOGS INHIBIT SEROTONIN AND DOPAMINE METABOLISM IN ISOLATED-MITOCHONDRIA

Daidzin, a major active principle of an ancient Chinese herbal treatme nt (Radix puerariae) for alcohol abuse, selectively suppresses ethanol intake in all rodent models tested, It also inhibits mitochondrial al dehyde dehydrogenase (ALDH-2), Studies on ethanol intake suppression a nd ALDH-2 inhibition by structural analogs of daidzin established a li nk between these two activities and suggested that daidzin may suppres s ethanol intake by inhibiting ALDH-2. ALDH-2 is a principal enzyme in volved in serotonin (5-HT) and dopamine (DA) metabolism, Thus, daidzin mag act by inhibiting 5-HT and DA metabolism, To evaluate this possib ility, we have studied the effect of daidzin and its analogs on 5-HT a nd DA metabolism in isolated hamster and rat liver mitochondria, Daidz in potently inhibits the formation of 5-hydroxyindole-3-acetic acid (5 -HIAA) and 3,4-dihydroxyphenylacetic acid (DOPAC) from their respectiv e amines in isolated mitochondria. Inhibition is concentration-depende nt and is accompanied by a concomitant accumulation of 5-hydroxyindole -3-acetaldehyde and 3,4-dihydroxyphenylacetaldehyde. Daidzin analogs t hat suppress hamster ethanol intake also inhibit 5-HIAA and DOPAC form ation, Comparing their effects on mitochondria-catalyzed 5-HIAA or DOP AC formation and hamster ethanol intake reveals a positive correlation -the stronger the inhibition on 5-HIAA or DOPAC formation, the greater the ethanol intake suppression, Daidzin and its active analogs, at co ncentrations that significantly inhibit 5-HIAA formation, have little or no effect on mitochondria-catalyzed 5-HT depletion, It appears that the antidipsotropic action of daidzin is not mediated by 5-HT (or DA) but rather by its reactive intermediates 5-hydroxyindole-3-acetaldehy de de and, presumably, 3,4-dihydroxyphenylacetaldehyde as well, which accumulates in the presence of daidzin.