The importance of alcohol dehydrogenase in regulation of ethanol metabolism in rat liver cells.
We used titration with the inhibitors tetramethylene sulphoxide and isobutyramide to assess quantitatively the importance of alcohol dehydrogenase in regulation of ethanol oxidation in rat hepatocytes. In hepatocytes isolated from starved rats the apparent Flux Control Coefficient (calculated assuming a single-substrate irreversible reaction with non-competitive inhibition) of alcohol dehydrogenase is 0.3-0.5. Adjustment of this coefficient to allow for alcohol dehydrogenase being a two-substrate reversible enzyme increases the value by 1.3-1.4-fold. The final value of the Flux Control Coefficient of 0.5-0.7 indicates that alcohol dehydrogenase is a major rate-determining enzyme, but that other factors also have a regulatory role. In hepatocytes from fed rats the Flux Control Coefficient for alcohol dehydrogenase decreases with increasing acetaldehyde concentration. This suggests that, as acetaldehyde concentrations rise, control of the pathway shifts from alcohol dehydrogenase to other enzymes, particularly aldehyde dehydrogenase. There is not a single rate-determining step for the ethanol metabolism pathway and control is shared among several steps.
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Department of Chemistry and Biochemistry, Massey University, Palmerston North, New Zealand.
Kitson
K E
KE
Hardman
M J
MJ
D000079:Acetaldehyde / Q000378:metabolism; D000426:Alcohol Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000577:Amides / Q000494:pharmacology; D000818:Animals; D000431:Ethanol / Q000378:metabolism*; D005502:Food; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D008297:Male; D008433:Mathematics; D010084:Oxidation-Reduction; D051381:Rats; D011919:Rats, Inbred Strains; D013217:Starvation / Q000201:enzymology; D013454:Sulfoxides; D013876:Thiophenes / Q000494:pharmacology
D000577:Amides; D013454:Sulfoxides; D013876:Thiophenes; C038166:tetramethylene sulfoxide; D000431:Ethanol; C030197:isobutyramide; D000426:Alcohol Dehydrogenase; D000079:Acetaldehyde