Daidzin suppresses ethanol consumption by Syrian golden hamsters without blocking acetaldehyde metabolism.
Daidzin is a potent, selective, and reversible inhibitor of human mitochondrial aldehyde dehydrogenase (ALDH) that suppresses free-choice ethanol intake by Syrian golden hamsters. Other ALDH inhibitors, such as disulfiram (Antabuse) and calcium citrate carbimide (Temposil), have also been shown to suppress ethanol intake of laboratory animals and are thought to act by inhibiting the metabolism of acetaldehyde produced from ingested ethanol. To determine whether or not daidzin inhibits acetaldehyde metabolism in vivo, plasma acetaldehyde in daidzin-treated hamsters was measured after the administration of a test dose of ethanol. Daidzin treatment (150 mg/kg per day i.p. for 6 days) significantly suppresses (> 70%) hamster ethanol intake but does not affect overall acetaldehyde metabolism. In contrast, after administration of the same ethanol dose, plasma acetaldehyde concentration in disulfiram-treated hamsters reaches 0.9 mM, 70 times higher than that of the control. In vitro, daidzin suppresses hamster liver mitochondria-catalyzed acetaldehyde oxidation very potently with an IC50 value of 0.4 microM, which is substantially lower than the daidzin concentration (70 microM) found in the liver mitochondria of daidzin-treated hamsters. These results indicate that (i) the action of daidzin differs from that proposed for the classic, broad-acting ALDH inhibitors (e.g., disulfiram), and (ii) the daidzin-sensitive mitochondrial ALDH is not the one and only enzyme that is essential for acetaldehyde metabolism in golden hamsters.
Keung
W M
WM
Center for Biochemical and Biophysical Sciences and Medicine, Harvard Medical School, Boston, MA 02115, USA.
Lazo
O
O
Kunze
L
L
Vallee
B L
BL
D000079:Acetaldehyde / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D000427:Alcohol Deterrents / Q000494:pharmacology*; D000428:Alcohol Drinking; D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D006224:Cricetinae; D004221:Disulfiram / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D007529:Isoflavones / Q000494:pharmacology*; D008647:Mesocricetus; D008930:Mitochondria, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D010084:Oxidation-Reduction
D000427:Alcohol Deterrents; D007529:Isoflavones; C013908:daidzin; D000444:Aldehyde Dehydrogenase; D000079:Acetaldehyde; D004221:Disulfiram