Shohei Matsuzaki

High blood acetaldehyde levels after ethanol administration. Difference between alcoholic and nonalcoholic subjects.

Blood actaldehyde and ethanol levels were measured in 11 subjects, six with chronic alcholoism and five nonalcholic controls, after alcohol had been given intravenously. Despite a progressive fall in blood ethanol over a range of 54 to 33 mM/acetaldehyde did not decrease in any of the 11 subjects. The mean acetaldehyde plateau level was significantly (p less than 0.001) higher in alcoholic (42.7 plus or minus 1.2 mum) than in nonalcoholic (26.5 plus or minus 1.5 mum) subjects. When the mean blood ethanol concentration reached 24 mM,the acetaldehyde plateau ended abruptly in each subject. The ethanol concentration at which this fall of blood acetaldehyde occurred suggests desaturation of an ethanol oxidizing system other than alcohol dehydrogenase and indicates that at high ethanol blood levels, such a system contributes to ethanol oxidation. The highet acetaldehyde levels in alcholism may result from both greater activity of this system and mitochondrial damage, and could contribut to the neurologic, hepatic and cardiac complications of alcoholism.

Increased susceptibility of hepatic mitochondria to the toxicity of acetaldehyde after chronic ethanol consumption.

Abstract Acetaldehyde at concentrations known to occur in vivo significantly depresses respiration with NAD-dependent substrates and oxidation of fatty acids to CO 2 in mitochondria of rats fed ethanol chronically. This toxic effect of acetaldehyde may explain, in part, the mechanism of progressive liver injury in the alcoholic.

[37] The Microsomal ethanol oxidizing systems (MEOS)

Publisher Summary This chapter describes procedures for assaying the activities of microsomal ethanol oxidizing system (MEOS) in total liver tissue, in microsomes, and in partially purified microsomal fractions. It is assumed that ethanol metabolism proceeds exclusively via alcohol dehydrogenase (ADH), an enzyme of the cell sap of the hepatocyte. Indeed, this concept is satisfactory at low ethanol concentrations because the oxidation of ethanol is almost completely abolished under these conditions by pyrazole, a potent inhibitor of alcohol dehydrogenase activity. Recent studies have shown that, in addition to ADH, ethanol can also be metabolized by the microsomal fraction of the hepatocyte, which comprises the endoplasmic reticulum. MEOS is also differentiated from ADH, in contrast to ADH the microsomal ethanol oxidation is more active with NADPH than with NAD, has a neutral pH optimum, and shows a relative insensitivity to the ADH inhibitors pyrazole and 4- methylpyrazole.

Effect of chronic alcohol consumption on ethanol and acetaldehyde metabolism.

Hepatic metabolism of ethanol to acetaldehyde by the alcohol dehydrogenase (ADH) pathway is associated with the generation of reducing equivalents as NADH. Conversely, reducing equivalents are consumed when ethanol oxidation is catalyzed by the NADPH dependent microsomal ethanol oxidizing system (MEOS). Since the major fraction of ethanol metabolism proceeds via ADH and since the oxidation of acetaldehyde also generates NADH, an excess of reducing equivalents is produced. This explains a variety of effects following acute ethanol administration, including hyperlactacidemia, hyperuricemia, enhanced lipogenesis and depressed lipid oxidation. To the extent that ethanol is oxidized by the alternate MEOS pathway, it slows the metabolism of other microsomal substrates. Following chronic ethanol consumption, adaptive microsomal changes prevail, which include enhanced ethanol and drug metabolism, and increased lipoprotein production. Eventually, injury develops with alterations of the rough endoplasmic reticulum and structural and functional abnormalities of the mitochondria.