Daidzin inhibits mitochondrial aldehyde dehydrogenase and suppresses ethanol intake of Syrian golden hamsters

Abstract

Daidzin is the major active principle in extracts of radix puerariae, a traditional Chinese medication that suppresses the ethanol intake of Syrian golden hamsters. It is the first isof lavone recognized to have this effect. Daidzin is also a potent and selective inhibitor of human mitochondrial aldehyde dehydrogenase (ALDH-2). To establish a link between these two activities, we have tested a series of synthetic structural analogs of daidzin. The results demonstrate a direct correlation between ALDH-2 inhibition and ethanol intake suppression and raise the possibility that daidzin may, in fact, suppress ethanol intake of golden hamsters by inhibiting ALDH-2. Hamster liver contains not only mitochondrial ALDH-2 but also high concentrations of a cytosolic form, ALDH-1, which is a very efficient catalyst of acetaldehyde oxidation. Further, the cytosolic isozyme is completely resistant to daidzin inhibition. This unusual property of the hamster ALDH-1 isozyme accounts for the fact we previously observed that daidzin can suppress ethanol intake of this species without blocking acetaldehyde metabolism. Thus, the mechanism by which daidzin suppresses ethanol intake in golden hamsters clearly differs from that proposed for the classic ALDH inhibitor disulfiram. We postulate that a physiological pathway catalyzed by ALDH-2, so far undefined, controls ethanol intake of golden hamsters and mediates the antidipsotropic effect of daidzin.The identification of pharmaceutical agents that selectively suppress compulsive human ethanol consumption has been a principal aim of biochemical and pharmacological studies of alcohol abuse, its causes, and control. However, the lack of a specific and well identified molecular target (receptor) for ethanol and a suitable animal model for human alcoholism have made this an elusive goal (1). While many central nervous system and ethanol-sensitizing agents have been shown to suppress the ethanol intake of animals commonly employed as models for the human problem, only acamprosate and naltrexone have been judged suitable for the treatment of this human ailment. Even those drugs are only marginally effective in a relatively minor segment of the aff licted population and then only when used in conjunction with psychotherapy (2-4). The manifestations of alcoholism are complex, encompassing both physical and psychiatric features seemingly unique to humans. Hence, it is not surprising that the extension of results from animal studies to the human situation has not resulted in the identification of agents that cure alcohol abuse.The search for new antidipsotropic agents, nevertheless, calls for a laboratory animal that voluntarily consumes ethanol, ideally in significant amounts. For this purpose, we have chosen the Syrian golden hamster (Mesocricetus auratus) because of its known natural preference to consume large quantities of ethanol compared with water and its predictive validity (5). Neither selective breeding, special training, nor the addition of dietary sweeteners is required to ma...

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Effects of Puerariae radix on Cell Proliferation and Nitric Oxide Synthase Expression in Dentate Gyrus of Alcohol-Intoxicated Sprague-Dawley Rats

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Effect of Puerariae radix on c-Fos Expression in Hippocampus of Alcohol-Intoxicated Juvenile Rats.

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