0 I45-6008/93/ zyxwvutsrqponm I zyxwvutsrqponmlkjihgfedcbaZYXWVUTS 70 I -0048$3.00/0 zyxwvutsrqp AI.(WIOI ISM: CI.INI(.AI. AND EXP1:RIML"TAI RESLARCH Vol. 17. No. I January/February I992 Determinants of Ethanol and Acetaldehyde Metabolism in Chronic Alcoholics Julian Panes, Joan Caballeria, Rairnon Guitart, Albert Pares, Xavier Soler, Miguel Rodarnilans, Miguel Navasa, Xavier Pares, Jaurne Bosch, and Joan Rodes We have studied the factors determining the rate of ethanol and acetaldehyde metabolism in a group of 25 alcoholics with varying degrees of liver lesion (from normal liver to cirrhosis) and in six nonalcoholiccirrhotics. In alcoholics the ethanol metabolic rate was related to hepatic function, estimated either by the aminopyrine breath test zyxwvutsrqpo (r = 0.70, p < 0.001) or the indocyaninegreen clearance (r = 0.76, p < 0.01), and was independent of the activity of hepatic alcohol dehydrogenase and hepatic blood flow. In nonalcoholic cir- rhotics blood acetaldehydewas always below the detection limit (0.5 zyxwvu PM), but elevated levels were found in 14 out of the 25 alcoholics. Alcoholics with elevated blood acetaldehyde showed a significantly higher ethanol metabolic rate than alcoholics with undetectable acetaldehyde(120 f 17 mg/kg/hr vs 104 f 11 mg/kg/hr, p < 0.02), but no differences were observed in the activities of alcohol and aldehyde dehydrogenases. Peak blood acetaldehyde levels were directly related to the ethanol metabolic rate (r = 0.48, p < 0.02), but not to activities of hepatic alcohol or aldehyde dehydrogenases. These results indicate that in chronic alcoholicsthe main determinant of the ethanol metabolic rate is hepatic function, while the rise of blood acetaldehyde is mainly dependent on the ethanol metabolic rate. Alcohol and aldehyde dehydrogenase activitiesdo not seem to be rate-limiting factors in the oxidation of ethanol or acetaldehyde. Key Words: Ethanol, Acetaldehyde, Hepatic Function, Alcohol Dehydrogenase,Aldehyde Dehydrogenase. HE MAIN SITE for ethanol metabolism is the liver Twhere it is enzymatically converted, first to acetalde- hyde and then to acetate, which is then metabolized peripherically to zyxwvutsrqp COr and H2O.' The principal enzymatic system involved in the conversion of ethanol to acetalde- hyde is alcohol dehydrogenase (ADH).' A subset of the microsomal mixed function oxidase system, known as the microsomal ethanol oxidizing system (MEOS) may pro- vide an important contribution to ethanol metabolism when blood ethanol levels are very high.3.4 The conversion of acetaldehyde to acetate is catalyzed by the aldehyde dehydrogenase (ALDH). Two main forms exist; the low K,,, isoenzyme located in the mitochondria plays a pre- From the Liver Unit (J. p., J. C., zyxwvutsrqpo A. p., M. N.. J. B. ~ J. R.) zyxwvutsr and Laboratory of Toxicology (R.G.. M.R.). Hospital Clinic i Provincial, Universitai dr Barcelona; and Department oJ Biochemistry and Molecrrlar Biology, Universirat Airtonoma de Barcelona (X.S., X.P.). Barcelona Spain. Receivedfiir publication April 13. 1992; accepted Jirly 22, I992 This sti1d.v was supported by grants .from CIRIT. Generalitat de Dr. J. Panes was the recipient of a riwarch grant Jrom the Hospital Reprint reqiiesis: Joan Cahalleria, M. D., Liver Unit. Ilospital Clinic. Copyright zyxwvutsrqp 0 I993 by The Research Society on Alcvholism. Calaliinya and.fiom CA YCIT (1404182). Clinic i provincial de Barcelona. i Provincial de Barcelona. Villarroel 170, 08036-Barcelona. Spain. 40 dominant role in maintaining very low concentrations of acetaldehyde in blood and liver tissue during the metab- olism of ethanol; the second form has a high K, for acetaldehyde and is located in the cyto~ol.~ Both ADH and ALDH exhibit multiple isoenzymatic forms6 and it has been shown that this variation may be responsible for individual and racial differences in sensitivity to Acetaldehyde is a highly toxic substance and is consid- ered as a mediator of alcoholic liver damage. There are several reports of raised blood acetaldehyde concentra- tions after intravenous or oral administration of ethanol in chronic alcoholics.'0-'6 Such an elevation may be ex- plained, either by increased ethanol or decreased acetal- dehyde oxidation, since both an increased rate of ethanol metaboli~rn"-'~ and a decrease of ALDH have been observed in alcoholics. In the present study we have investigated the influence of hepatic function and ADH activity on the kinetics of ethanol elimination after intravenous ethanol administra- tion in patients with alcoholic and nonalcoholic liver disease. We have also evaluated the respective roles of enhanced ethanol elimination and the activities of hepatic ADH and ALDH in the elevation of acetaldehyde levels. MATERIALS AND METHODS The study population was comprised of 25 patients with alcoholic liver disease and six patients with nonalcoholic liver disease. The alco- holic patients had consumed more than 80 g of ethanol daily for at least 5 years, and had been drinking at least 10 days before the studies. None of the nonalcoholic patients had drunk more than 30 g of alcohol daily and all had been abstinent for the previous 6 months. The patients of the present study are part of those included in a previously published study in which only activities of alcohol metabolizing enzymes were analyzed in a larger group of patient^.'^ Standard liver function tests and a percutaneous liver biopsy were performed in all patients. Part of the tissue obtained was used for histologic diagnosis: the remaining part was frozen in liquid nitrogen and stored at -7o'C until enzyme analysis. According to the histologic diagnosis alcoholic patients were divided into five groups: (I) normal liver or minimal changes (4). (2) steatosis (4). (3) fibrosis (4), (4) alcoholic hepatitis (7). and (5) cirrhosis (6): definition criteria of these lesions has been previously stated. All nonalcoholic patients had cirrhosis. In all alcoholic patients liver function was precisely determined by the aminopyrine breath test following the method described by Hepner and Ve~ell.'~ In 1 I alcoholics hepatic hemodynamics were studied. After hepatic vein catheterization in these patients, a solution of indocyanine green (Serb, Paris) was infused intravenously at a constant rate of 0.3 rnglmin after a priming dose of 10 mg. Following an equilibration period of 40 min. four samples of peripheral and hepatic venous blood were .lk~oh~l~'lrn I;tp Re\. Vol 17. No I. 1993: pp48-53