Daidzin and its antidipsotropic analogs inhibit serotonin and dopamine metabolism in isolated mitochondria.

Abstract

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.

• Authors: W M Keung, B L Vallee
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 95 Issue 5 Pg. 2198-203 (Mar 03 1998) ISSN: 0027-8424 [Print] United States
• PMID: 9482862 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Alcohol Deterrents
• Dopamine Antagonists
• Enzyme Inhibitors
• Isoflavones
• Serotonin Antagonists
• 3,4-Dihydroxyphenylacetic Acid
• Serotonin
• daidzin
• Hydroxyindoleacetic Acid
• Alcohol Dehydrogenase
• Aldehyde Reductase
• Monoamine Oxidase
• Dopamine
• puerarin

Topics

• 3,4-Dihydroxyphenylacetic Acid (metabolism)
• Alcohol Dehydrogenase (antagonists & inhibitors, metabolism)
• Alcohol Deterrents (pharmacology)
• Aldehyde Reductase (metabolism)
• Animals
• Cricetinae
• Dopamine (metabolism)
• Dopamine Antagonists (pharmacology)
• Enzyme Inhibitors (pharmacology)
• Hydroxyindoleacetic Acid (metabolism)
• Isoflavones (pharmacology)
• Male
• Mesocricetus
• Mitochondria, Liver (drug effects, metabolism)
• Monoamine Oxidase (metabolism)
• Rats
• Rats, Wistar
• Serotonin (metabolism)
• Serotonin Antagonists (pharmacology)
• Species Specificity
• Structure-Activity Relationship