Abstract
Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) are principal enzymes responsible for metabolism of ethanol in mammals. The steady-state metabolic flux of ethanol has been poorly understood. We investigated flux rates of the individual steps of ethanol metabolism in perfused rat livers treated with ALDH inactivator cyanamide as an attempt to mimic human ALDH2 deficiency commonly seen in East Asians. The net rates of ethanol oxidation, acetaldehyde oxidation, and acetate activation were determined with a set of defined equations, based on the set influx rates of ethanol and the measured efflux rates of ethanol, acetaldehyde, and acetate. After intraperitoneal injections of 0.2 and 1.5mg/kg cyanamide, hepatic activities of mitochondrial ALDH2 and cytoplasmic ALDH1A1 decreased to a similar degree, that is, 51 to 57% and 69 to 74%, compared with the corresponding controls, respectively, whereas cytoplasmic ADH1 activity remained unchanged. At infusing 2mM ethanol, acetaldehyde oxidation rate well matched (99%) the net ethanol oxidation rate in control liver. Both the ethanol and acetaldehyde oxidation rates were significantly decreased after cyanamide treatments. At 10mM ethanol, the efflux acetaldehyde was significantly higher than that infusing 2mM ethanol in both control and cyanamide groups. Seventy-eight percent of the oxidized ethanol released as efflux acetate. At 2mM ethanol, the apparent flux control coefficients of ADH1 were assessed to be 0.78, 0.54, and 0.39, respectively, in control, low, and high cyanamide-treated livers. Kinetic simulations revealed that inhibition by acetaldehyde may largely account for the observed reduction of ADH1 oxidation rates after cyanamide treatment. Our results provide the first flux evidence that ADH and ALDH are steps influencing steady-state metabolism of ethanol in rat livers with inactivated ALDHs.
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