The roles of the hepatocellular redox state and the hepatic acetaldehyde concentration in determining the ethanol elimination rate in fasted rats.
Ethanol administration (2 g/kg i.p.) to fasted male Wistar rats caused, on average, a 64% decrease in the cytosolic free NAD+:NADH ratio and a 41% decrease in the mitochondrial free NAD+:NADH ratio measured 90 min after ethanol was injected. Treatment of animals with either Naloxone (2 mg/kg i.p.) 1 hr after ethanol or 3-palmitoyl-(+)-catechin (100 mg/kg p.o. 1 hr before ethanol) prevented these ethanol induced redox state changes, without affecting the ethanol elimination rate or the hepatic acetaldehyde concentration measured at 90 min after ethanol administration. The thiol compounds cysteine and malotilate (diisopropyl-1,3-dithiol-2-ylidene malonic acid) significantly lowered the hepatic acetaldehyde concentrations measured at 0.75, 1.5 and 6.0 hr after ethanol, and caused a 29% and 12% increase respectively in the ethanol elimination rate, without affecting the ethanol induced alterations in the NAD+:NADH ratio. Pretreatment of animals with the aldehyde dehydrogenase inhibitor, cyanamide (1 mg/kg or 15 mg/kg p.o. one hour before ethanol), caused increases of up to 23-fold in the hepatic acetaldehyde level, without influencing the cytosolic NAD+:NADH ratio in ethanol dosed rats, while significantly reducing the ethanol elimination rate by up to 44%, compared with controls. These results suggest that ethanol oxidation by cytosolic alcohol dehydrogenase may be regulated in part by the hepatic acetaldehyde concentration achieved during ethanol metabolism rather than NADH reoxidation, either to supply NAD for the dehydrogenase, or to reduce inhibition of the enzyme by NADH, being a rate-limiting factor in ethanol metabolism in fasted rats.
Ryle
P R
PR
Chakraborty
J
J
Thomson
A D
AD
D000079:Acetaldehyde / Q000378:metabolism*; D000426:Alcohol Dehydrogenase; D000429:Alcohol Oxidoreductases / Q000378:metabolism; D000818:Animals; D002392:Catechin / Q000031:analogs & derivatives / Q000494:pharmacology; D003484:Cyanamide / Q000494:pharmacology; D003545:Cysteine / Q000494:pharmacology; D003600:Cytosol / Q000378:metabolism; D000431:Ethanol / Q000097:blood* / Q000494:pharmacology; D005215:Fasting; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008314:Malonates / Q000494:pharmacology; D008930:Mitochondria, Liver / Q000378:metabolism; D009243:NAD / Q000378:metabolism*; D009270:Naloxone / Q000494:pharmacology; D010084:Oxidation-Reduction; D051381:Rats; D011919:Rats, Inbred Strains
D008314:Malonates; D009243:NAD; D009270:Naloxone; D000431:Ethanol; D003484:Cyanamide; C036106:3-palmitoylcatechin; D002392:Catechin; D000429:Alcohol Oxidoreductases; D000426:Alcohol Dehydrogenase; D000079:Acetaldehyde; D003545:Cysteine; C024808:diisopropyl 1,3-dithiol-2-ylidenemalonate