Abstract
Previous studies in our laboratory (1–3), have indicated that the major rate limiting factor in ethanol metabolism in the intact liver cell is the rate of mitochondrial reoxidation to NAD+ of NADH produced in the oxidation of ethanol. This has now been confirmed in several laboratories (4–8). In this process oxygen is utilized and water is formed. The capacity of mitochondria to oxidize reducing equivalents is related to the relative availability of phosphate acceptor (ADP), or more generally to the phosphorylation potential (ATP/ADP × Pi) (9–12). Mitochondrial uncouplers such as dinitrophenol (DNP), carbonyl cyanide p-trifluoromethoxyphenyl-hydrazone (FCCP) and arsenate allow the mitochondria to oxidize reducing equivalents independently of phosphate acceptor availability and thus they increase the rate of oxygen consumption (13). Accordingly, the rate of ethanol metabolism has been shown to be increased by uncoupling agents both in vivo (2,4) and in vitro in liver slices (1, 14), perfused liver (3,5) and isolated hepatocytes (8). Figure 1 shows the effect of DNP on the rate of ethanol metabolism by perfused rat liver.
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VIDELA L and ISRAEL Y: Factors that modify the metabolism of ethanol in rat liver and adaptive changes produced by its chronic administration. Biochem J 118: 275–281, 1970
ISRAEL Y, KHANNA JM and LIN R: Effect of 2.4 — dinitrophenol on the rate of ethanol elimination in the rat in vivo. Biochem J 120: 447–448, 1970
SEIDEN H, ISRAEL Y and KALANT H: Activation of ethanol metabolism by 2.4 — dinitrophenol in the isolated perfused rat liver. Biochem Pharmacol 23: 2234–2337, 1974
KREBS HA and STUBBS M: Factors controlling the rate of alcohol disposal by the liver. In Alcohol Intoxication and Withdrawal, vol II, MM Gross (ed.). Plenum Press, N.Y. 1975. pp. 149
ERIKKSON CJ, LINDROS KO and FORSANDER OA: 2.4 — dinitrophenol-induced increase in ethanol and acetaldehyde oxidation in the perfused liver. Biochem Pharmacol 23: 2193, 1964
THURMAN RG, McKENNA WR and McCAFFREY TB: Pathwaysreponsible for the adaptive increase in ethanol utilization following chronic treatmentwith ethanol: Inhibitor studies with hemoglobin — free perfused liver. Molec Pharmacol 12: 156, 1976
CARTER EA and ISSELBACHER KJ: The effect of ethyl-x-chloro-phenoxisobutyrate. Life Sci 13: 907/1973
MAIJER AJ, VAN WOERKOM GM, WILLIAMSON JR and TAGER JM: Rate-limiting factors in the oxidation of ethanol by isolated rat liver cells. Biochem J 150: 205, 1975
CHANCE B and WILLIAMS GR: The respiratory chain and oxidativephosphorylation. Adv Enzymol 17: 65, 1956
CHANCE B and MIATRA PK: Determination of the intracellular phosphate potential of ascites cells by reversed electron transfer. In Control Mechanisms in Respiration and Fermentation, B Wright (ed). Ronald Press, N.Y., 1963. pp. 307
KLINGENBERG M: The respiratory chain. In Biological Oxidations, TP Singer (ed.). Interscience, N.Y., 1958. pp. 3
KLINGENBERG M: Respiratory control as function of the phosphorylation potential. In The Energy Level and Metabolic Control in Mitochondria, S Papa, JM Tager, E Quagliariello and EC Slater (eds.). Adriatica Editrica Bari, 1969. pp. 189
MAHLER HR and CORDES EH: Biological Chemistry, Harper and Row, N.Y., 1966
ISRAEL Y, VIDELA L, VIDELA-FERNANDEZ V and BERNSTEIN J: Effects of chronic ethanol treatment and thyroxine administration on ethanol metabolism and liver oxidative capacity. J Pharmacol ExpTher 192: 565, 1975
VIDELA L, FLATTERY KV, SELLERS EA and ISRAEL Ys Ethanol metabolism and liver oxidative capacity in cold acclimation. J Pharmacol Exp Ther 192: 575, 1975
LESTER C and KEOKOSKY WZ: Alcohol metabolism in the horse. Life Sci Part I 6: 2313, 1967
TYGSTRUP N, WINKLER K and LUNDQUIST F: The mechanism of the fructose effect on the ethanol metabolism of the human liver. J Clin Invest 44: 817, 1965
FORSANDER OA: Effects of ethanol on metabolic pathways. In International Encyclopedia of Pharmacology and Therapeutics, J. Tremolieres (ed). Pergamon Press, N.Y., 1970. Section 20, pp. 117
WILLIAMSON JR, SCHOLZ R, BROWNING ET, THURMAN RG, and FUKAMI MH: Metabolic effects of ethanol in perfused rat liver. J Biol Chem 244: 5044, 1969
FORSANDER OA and HIMBERT JJ: Effect of glucose on liver metabolism during ethanol oxidation. Metabolism 18: 776, 1969
HAWKINS RD, KALANT H and KHANNA JM: Effects of chronic intake of ethanol on the rate of ethanol metabolism. Can J Pharmacol 44: 241, 1966
KATER RM, CARULLI N and IBER F: Differences in the rate of ethanol metabolism in recently drinking alcoholic and non-drinking subjects. Am J Clin Nutr 22: 1608, 1969
MEZEY E: Duration of the enhanced activity of the microsomal ethanol oxidizing system and rate of ethanol degradation in ethanol fed rats after withdrawal. Biochem Pharmacol 21: 137, 1972
MISRA PS, LEFEVRE A, ISHII H, RUBIN E and LIEBER CS: Increase of ethanol, meprobamate and pentobarbital metabolism after chronic ethanol administration in man and in rats. Am J Med 51: 346, 1971
PIEPER WA and SKEEN MJ: Changes in the rate of ethanol elimination associated wtih chronic administration of ethanol to chimpanzees and Rhesus monkeys. Drug Metabolism and Disposition 1: 634, 1973
UGARTE G and VALENZUELA J: Mechanisms of liver and pancreas damage in man. In Biological Basis of Alcoholism, Y Israel and J Mardones (eds). Wiley, N.Y., 1971. Chapter 5
VIDELA L, BERNSTEIN J and ISRAEL Y: Metabolic alternations produced in the liver by chronic ethanol administration. Increased oxidative capacity. Biochem J 134: 507, 1973
TOBON F and MEZEY E: Effect of ethanol administration on hepatic ethanol and drug-metabolizing enzymes and on rates of ethanol degradation. J Lab Clin Med 77: 110, 1971
LIEBER CS and DE CARLI LM: Hepatic microsomal ethanol oxidizing system. In vitro characteristics and adaptive properties in vivo. J Biol Chem 245: 2505, 1970
ISRAEL Y, VIDELA L and BERNSTEIN J: Hypermetabolic state after chronic ethanol consumption. Hormonal interrelations and pathogenic implications. Fed Proc 34: 2052, 1975
EDMONSON HA, PETERS RL, TELFER BR, REYNOLDS RB and KUZMA OT: Sclerosing hyaline necrosis of the liver in the chronic alcoholic. Ann Inter Med 59: 646, 1963
EDMONSON H, PETERS RL, FRANKEL HH and BOROWSKY S: The early stage of liver injury in the alcoholic. Medicine 46: 119, 1967
SCHAFFNER F and POPPER H: Alcoholic hepatitis in the spectrum of ethanol — induced liver injury. Scand J Gastroenterol (Suppl 7) 5: 69, 1970
JEWELL LD, MEDLINE A and MEDLINE NM: Alcoholic hepatitis. Can Med Assoc J 105: 711, 1971
REYNOLDS TB and EDMONSON HA: Alcoholic hepatitis. Ann Int Med 74: 440, 1971
RAPPAPORT AM: The microcirculatory hepatic unit. Microvasc Res 6: 212, 1973
ISRAEL Y, KALANT H, ORREGO H, KHANNA JM, VIDELA L, and PHILLIPS MJ: Experimental alcohol-induced hepatic necrosis: Suppression by propylthiouracil. Proc Natl Acad Sci (USA) 72: 1137, 1975
KHANNA JM, KALANT H and BUSTOS G: Effects of chronic intake of ethanol on rate of ethanol metabolism, II. Can J Physiol Pharmacol 45: 777, 1967
BECKETT AG, LIVINGSTONE AV and HILL KR: Acute alcoholic hepatitis. Brit Med J 2: 1113, 1961
HARINASUTA U and ZIMMERMAN HJ: Alcoholic steatonecrosis I. Relationship between severity of hepatic disease and presence of Mallory bodies in the liver. Gastroenterology 60: 1031, 1971
BIRSCHBACH HR, HARINASUTA U and ZIMMERMAN HJ: Alcoholic Steatonecrosis. II. Prospective study of prevalence of Mallory bodies in biopsy specimens and comparison of severity of hepatic disease in patients with and without this histological feature. Gastroenterol 66; 1195, 1974
GREEN J, MISTILIS S and SCHIFF L: Acute alcoholic hepatitis. Arch Int Med 112; 67, 1963
HANDBOOK OF PHYSIOLOGY, Section 7, Endocrinology, vol III. Am Physiol Soc. Washington, 1974
In Spontaneous Hypertension, its Pathogenesis and Complications, K Okamoto (ed.). Springer-Verlag, N.Y., 1972
ALBRECHT I, VIZEK M and KRECEK J: The hemodynamics of the rat during ontogenesis, with special reference to the age factor in the development of hypertension. In Spontaneous Hypertension, its Pathogenesis and Complications, K. Okamoto (ed). SpringerVerlag, N.Y., 1972. pp. 121
AOKI K: Experimental studies on the relationship between endocrine organs and hypertension in spontaneously hypertensive rats, III. Role of the endocrine organs and hormones. Jap Heart J 5: 57, 1964
FOLKOW B, HALLBACK M, LUNDGREN Y, SILVERTSSON R and WEISS L: The importance of adaptive changes in vascular design for the establishment and maintenance of primary hypertension as studied in man and in spontaneously hypertensive rat. In Spontaneous Hypertension, its Pathogenesis and Complications, K. Okamoto (ed). Springer-Verlag, N.Y., 1972. pp. 103
FOLKOW B, HALLBACK M and WEISS L: Cardiovascular responses to acute mental stress in spontaneously hypertensive rats. Clin Sci and Molec Med 45: 1315, 1973
BERNSTEIN J, VIDELA L and ISRAEL Y: Hormonal influences in the development of the hypermetabolic state of the liver produced by chronic administration of ethanol. J Pharmacol Exp Ther 192: 583, 1975
BERNSTEIN J, VIDELA L and ISRAEL Y: Role of the sodium pump in the regulation of liver metabolism in experimental alcoholism. Ann New York Acad Sci 242: 560, 1974
CONN HO: Therapy of alcoholic liver disease. In Alcohol and Abnormal Protein Biosynthesis, M.A. Rothschild, M. Oratz and S.S. Schreiber (eds). Pergamon Press, N.Y., 1975. pp. 509
LISHNER MW, ALEXANDER JF and GALAMBOS JT: Natural history of alcoholic hepatitis. I. The acute disease. Am J Digest Pis 16: 481, 1971
FALLON HJ: Alcoholic liver disease. In Alcohol and Abnormal Protein Biosynthesis, MA Rothschild, M Oratz and SS Schreiber (eds). Pergamon Press, N.Y., 1975. pp. 473
JEFFRIES GH: Gastritis. In Gastrointestinal Disease, Pathophysiology, Diagnosis, Management, MH Sleisenger and JS Fordtran (eds). Saunders, Philadelphia, 1973. pp. 560
DAVENPORT HW: Gastric mucosal hemorrhage in dogs. Effects of acid, aspirin and alcohol. Gastroenterol. 56: 439, 1969
IVEY KJ: Gastritis. Med Clin North Amer 58: 1289, 1974
LEEVY CM and ZETTERMAN RK: Malnutrition and alcoholism — An overview. In Alcohol and Abnormal Protein Biosynthesis, MA Rothschild, M Oratz and S Schreiber (eds). Pergamon Press, N.Y., 1975. pp. 3
LEEVY CM, VALDELLON E and SMITH F: Nutritional factors in alcoholism and its complications. In Biological Basis of Alcoholism, Y Israel and J Mardones (eds). Wiley, N.Y., 1971. pp. 365
EICHNER ER: The hematologic disorders of alcoholism. Am J Med 54: 621, 1973
HINES JD and COWAN DH: Anemia in alcoholism. In Drugs and Hematological Reactions, NV Dimitrov and JH Nodine (eds). Grunne and Stratton, N.Y., 1974. pp. 141
HERBERT V and TISMAN G: Hematological effects of alcohol. Ann New York Acad Sci 252: 307, 1975
VICTOR M: The role of hypomagnesemia and resiratory alkalosis in the genesis of alcohol withdrawal symptoms. Ann New York Acad Sci 215: 235, 1973
SERENY G, RAPOPORT A and HUSDAN H: The effect of ethanol withdrawal on electrolyte and acid-base balance. Metabolism 15: 896, 1966
TERRITO MC and TANAKA KR: Hypophosphatemia in chronic alcoholism. Arch Int Med 134: 445, 1974
GOODMAN LS and GILMAN A (eds). In The Pharmacological Basis of Therapeutics. MacMillan, N.Y., 1975. pp. 138
RANKIN JG and WILKINSON P: Alcohol and tobacco smoking. In The Health of a Metropolis, J. Krupinski and A. Stoller (eds). Heineman Educational Australia, 1971
LAMBERTSEN CJ: Effects of excessive pressures of oxygen, nitrogen, carbon dioxide and carbon monoxide: implications in aerospace, undersea and industrial environments. In Medical Physiology 13th Ed., V.B. Mountcasle (ed). Mosby, Saint Louis, 1974. pp. 1563
WALD N, HOWARD S, SMITH PG and BAILEY A: Use of carboxy-haemoglobin levels to predict the development of diseases associated with cigarette smoking. Thorax 30: 133, 1975
EMIRGIL C, SOBOL BJ, HEYMANN B and SHIBUTANI K: Pulmonary function in alcoholics. Amer J Med 57: 69, 1974
SMITH F and PALMER DL: Alcoholism, infection and altered host defenses: A review of clinical and experimental observations. J Chron Pis 29: 35, 1976
CHOMET B and GACH BM: Lobar pneumonia and alcoholism: An analysis of thirty seven cases. Amer J Med Sci 253: 300, 1967
TILLOTSON JR and LERNER AM: Characteristics of pneumonias caused by Escherichia coli. New Engl J Med 277: 115, 1967
JOHNSON WP, KAYE P and HOOK EW: Hemophilus influenza pneumonia in adults. Amer Rev Resp Pis 97: 1112, 1968
LIEBER CS and PE CARLI LM: Animal models of ethanol dependence and liver injury in rats and baboons. Fed Proc 35: 1232, 1976
BURCH GE and PE PASCUALE NP: Alcoholic cardiomyopathy. Am J Cardiol 23: 723, 1969
ABELM AN WH and RAMIREZ A: Alcoholic cardiovascular disease. In Alcohol and Abnormal Protein Biosynthesis, MA Rothschild, M Oratz and SS Schreiber (eds). Pergamon Press, N.Y., 1975. pp. 459
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Israel, Y., Orrego, H., Khanna, J.M., Stewart, D.J., Phillips, M.J., Kalant, H. (1977). Alcohol Induced Susceptibility to Hypoxic Liver Damage: Possible Role in the Pathogenesis of Alcoholic Liver Disease?. In: Fisher, M.M., Rankin, J.G. (eds) Alcohol and the Liver. Springer, Boston, MA. https://doi.org/10.1007/978-1-4613-4184-0_21
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