The mitochondrial monoamine oxidase-aldehyde dehydrogenase pathway: A potential site of action of daidzin

Recent studies showed that daidzin suppresses ethanol intake in ethanol-pre ferring laboratory animals. In vitro, it potently and selectively inhibits the mitochondrial aldehyde dehydrogenase (ALDH-2). Further, it inhibits the conversion of monoamines such as serotonin (5-HT) and dopamine (DA) into t heir respective acid metabolites, 5-hydroxyindole-3-acetic acid (5-HIAA) an d 3,4-dihydroxyphenylacetic acid (DOPAC) in isolated hamster or rat liver m itochondria. Studies on the suppression of ethanol intake and inhibition of 5-HIAA (or DOPAC) formation by six structural analogues of daidzin suggest ed a potential link between these two activities. This, together with the f inding that daidzin does not affect the rates of mitochondria-catalyzed oxi dative deamination of these monoamines, raised the possibility that the eth anol intake-suppressive (antidipsotropic) action of daidzin is not mediated by the monoamines but rather by their reactive biogenic aldehyde intermedi ates such as 5-hydroxyindole-3-acetaldehyde (5-HIAL) and/or 3,4-dihydroxyph enylacetaldehyde (DOPAL) which accumulate in the presence of daidzin. To fu rther evaluate this possibility, we synthesized more structural analogues o f daidzin and tested and compared their antidipsotropic activities in Syria n golden hamsters with their effects on monoamine metabolism in isolated ha mster liver mitochondria using 5-HT as the substrate. Effects of daidzin an d its structural analogues on the activities of monoamine oxidase (MAO) and ALDH-2, the key enzymes involved in 5-HT metabolism in the mitochondria, w ere also examined. Results from these studies reveal a positive correlation between the antidipsotropic activities of these analogues and their abilit ies to increase 5-HIAL, accumulation during 5-HT metabolism in isolated ham ster liver mitochondria. Daidzin analogues that potently inhibit ALDH-2 but have no or little effect on MAO are most antidipsotropic, whereas those th at also potently inhibit MAO exhibit little, if any, antidipsotropic activi ty. These results, although inconclusive, are consistent with the hypothesi s that daidzin may act via the mitochondrial MAO/ALDH pathway and that a bi ogenic aldehyde such as 5-HIAL may be important in mediating its antidipsot ropic action.