Daidzin and its antidipsotropic analogs inhibit serotonin and dopamine metabolism in isolated mitochondria.
Daidzin, a major active principle of an ancient Chinese herbal treatment (Radix puerariae) for alcohol abuse, selectively suppresses ethanol intake in all rodent models tested. It also inhibits mitochondrial aldehyde dehydrogenase (ALDH-2). Studies on ethanol intake suppression and ALDH-2 inhibition by structural analogs of daidzin established a link between these two activities and suggested that daidzin may suppress ethanol intake by inhibiting ALDH-2. ALDH-2 is a principal enzyme involved in serotonin (5-HT) and dopamine (DA) metabolism. Thus, daidzin may act by inhibiting 5-HT and DA metabolism. To evaluate this possibility, we have studied the effect of daidzin and its analogs on 5-HT and DA metabolism in isolated hamster and rat liver mitochondria. Daidzin potently inhibits the formation of 5-hydroxyindole-3-acetic acid (5-HIAA) and 3,4-dihydroxyphenylacetic acid (DOPAC) from their respective amines in isolated mitochondria. Inhibition is concentration-dependent and is accompanied by a concomitant accumulation of 5-hydroxyindole-3-acetaldehyde and 3, 4-dihydroxyphenylacetaldehyde. Daidzin analogs that suppress hamster ethanol intake also inhibit 5-HIAA and DOPAC formation. Comparing their effects on mitochondria-catalyzed 5-HIAA or DOPAC 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 concentrations 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-acetaldehyde and, presumably, 3, 4-dihydroxyphenylacetaldehyde as well, which accumulates in the presence of daidzin.
Keung
W M
WM
Center for Biochemical and Biophysical Sciences and Medicine, Harvard Medical School, 250 Longwood Avenue, Boston, MA 02115, USA.
Vallee
B L
BL
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000426:Alcohol Dehydrogenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000427:Alcohol Deterrents / Q000494:pharmacology*; D000449:Aldehyde Reductase / Q000378:metabolism; D000818:Animals; D006224:Cricetinae; D004298:Dopamine / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D007529:Isoflavones / Q000494:pharmacology*; D008297:Male; D008647:Mesocricetus; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism*; D008995:Monoamine Oxidase / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D013045:Species Specificity; D013329:Structure-Activity Relationship
D000427:Alcohol Deterrents; D018492:Dopamine Antagonists; D004791:Enzyme Inhibitors; D007529:Isoflavones; D012702:Serotonin Antagonists; D015102:3,4-Dihydroxyphenylacetic Acid; D012701:Serotonin; C013908:daidzin; D006897:Hydroxyindoleacetic Acid; D000426:Alcohol Dehydrogenase; D000449:Aldehyde Reductase; D008995:Monoamine Oxidase; D004298:Dopamine; C033607:puerarin