Frank Lundquist

Utilization of Acetate in the Human Forearm during Exercise after Ethanol Ingestion

The uptake of acetate in the human forearm was studied in five fasting (14 h) subjects during 10-min periods of ergometer work at 7 and 10 kilopond-meters per minute (kpm/min). A constant arterial acetate concentration was established by administration of a small quantity of alcohol (25 g) to the subjects after a control work period. Blood flow was measured by an indicator dilution technique. Acetate uptake varied linearly with the product of arterial acetate concentration and blood flow. Acetate metabolism was calculated to account for about 6.5% of the energy metabolism, assuming complete combustion to carbon dioxide and water. Oxygen uptake and blood flow did not change in the presence of acetate and ethanol. After administration of ethanol the arterial concentrations of FFA and glycerol decreased to about half, whereas the lactate concentration increased to about twice the control values, confirming other reports. Glucose utilization was increased and lactate output decreased during the ethanol periods, presumably a consequence of the changing arterial concentrations and increased insulin level. Measurements of the arterial and venous lactate/pyruvate concentration ratios indicate that the NAD-mediated cytoplasmic redox state in the muscle is not changed in the presence of acetate and ethanol.

Glycerol Metabolism in the Human Liver: Inhibition by Ethanol

Glycerol is metabolized predominantly in the liver, the first step presumably being phosphorylation to α-glycerophosphate. When ethanol is present in the blood the rate of glycerol uptake by the splanchnic organs is reduced to about one-third of the control value. At the same time glycerophosphate accumulates in the liver. Hepatic blood flow and oxygen consumption are not influenced by the combined infusion of glycerol and ethanol. The phenomenon may be connected with the increased concentration of the reduced form of diphosphopyridine nucleotide present in the liver during ethanol metabolism.

INTERFERENCE OF ETHANOL IN CELLULAR METABOLISM

Alcohol is both a rapidly metabolized nutrient and a dangerous drug, depending on the amount consumed and the duration of the exposure t o the substance. This ambiguity is the cause of many difficulties in the interpretation of the results of alcohol consumption. It appears t o be a useful assumption that the physiological and biochemical actions of ethanol on the tissues and cells of the organism can be separated into 2 quite distinct groups. One group includes the direct and indirect consequences of ethanol metabolism, which are seen already at very low ethanol concentrations. The other group may be summarized as the pharmacological actions of alcohol. These are much less specific and are independent of the metabolism of ethanol itself. They become manifest only a t high concentrations and are indeed similar to the actions of a large number of substances, chemically only remotely related t o ethanol. Inevitably there is a considerable concentration range in which both types of action are observed, but one may suggest that a t concentrations that produce n o measurable changes in the physiological (or psychological) parameters the effects caused by alcohol metabolism are predominant, while a t concentrations in the range above 50 mM (200 mg/100 ml blood) the pharmacological actions are clearly manifest. As the specific reactions of a number of organs and tissues are considered in the following lectures by experts in these fields, I shall restrict my contribution to more general remarks, though of course specific examples will be given.

Acetaldehyde and aldehyde dehydrogenases—central problems in the study of alcoholism

In all known mechanisms for the biological oxidation of ethanol, the first enzymatic step is the formation of acetaldehyde which is further oxidized by a separate group of enzymes, mainly NAD(P), requiring dehydrogenases. Examples are known, however, of enzymatic oxidation of primary alcohol groups in other substances to the corresponding carboxylic acids without liberation of the intermediate aldehyde in the free state. The oxidation of UDP-glucose to UDP-glucuronate is one such example, but there are no indications of a similar mechanism in the case of ethanol. The concentration of acetaldehyde in the blood during alcoholaemia and the properties and location of the enzymes responsible for the removal of acetaldehyde have been subjects of remarkable disagreement between the workers in the field. For instance, the blood acetaldehyde concentration in human subjects after alcohol ingestion reported in the literature varies from less than 1 pmol/l up to several hundred pmol/l blood. Acetaldehyde has been incriminated as a noxious substance which causes some of the unpleasant effects (e.g., flushing and nausea) and also the more serious consequences of alcohol intake-addiction, abstinence and hepatotoxicity. Condensation reactions between acetaldehyde and a number of neurotransmitters such as catecholamines, dopamine and serotonin take place spontaneously with formation of substances with chemical and physiological similarity to alkaloids like morphine and harmaline. Some of these condensation products have in fact been identified in human tissues and urine, but their origin from ethanol and their postulated significance in alcohol addiction and abstinence reactions have not yet been established. On this background, it is obviously important to know the true concentration of acetaldehyde in the blood and to know whether this is dependent on the habitual and actual alcohol consumption of the subject. During the last two or three years, it has become increasingly evident that analytical difficulties are responsible for the large discrepancies and especially for the very high acetaldehyde concentrations reported by some earlier workers. The analytical problems are quite complex. Acetaldehyde might be firmly bound to proteins and other substances in the biological mater-

The Chemical Nature of Fetal Albumin

Several observers have reported that serum albumin from the human fetus and newborn infants has a decreased capability for binding bilirubin and certain drugs, when compared with serum albumin from healthy adults,1 (and references therein). Decreased binding is also seen in pregnant women.2 The chemical nature of the binding defect has remained unknown.

Metabolism of Ethanol and the Effect of Ethanol on Metabolism

It may appear surprising in view of the spectacular advances made in biology in recent years that the chemically simple process, the oxidation of ethanol via acetaldehyde to acetate, is still not sufficiently known with regard to biochemical mechanisms, localization in the body, and effects on the metabolism of other substances. In 1919, Mellanby showed that the concentration of ethanol in the blood of human subjects after a single dose decreased in a linear way for many hours (1). Widmark later made a careful study of the absorption, distribution and elimination kinetics of alcohol, which led to the extensive use in Scandinavia of blood alcohol determinations for forensic purposes (2). Lundsgaard showed that the liver is by far the most important organ for elimination of ethanol (3). Moreover, he faced the fact that ethanol is a nutrient which on average provides a considerable proportion of the energy needed for the human body, 10–15% in the case of Danish population. He also pointed out that only about 40% of the total metabolism can be met by the oxidation of alcohol. In the last decade or so interest in various aspects of alcohol metabolism has been increasing, partly because of the practical importance, but also because it involves some biochemically fundamental problems.

The Use of Tritium and 14C Labelled Ethanol in Studies of Ethanol Metabolism at High Ethanol Concentrations

Measurement of the rate of ethanol metabolism of the liver at concentrations at which the pharmacological actions of ethanol become manifest, i.e. 50–80 mM are of considerable importance. Such measurements can, however, not be performed with acceptable accuracy by determination of the decrease in ethanol concentration in preparations such as slices, isolated hepatocytes, or perfused liver, as the concentration differences are small compared to the absolute level. In the intact organism the overall metabolism of ethanol at high concentrations can be determined by measurement of the blood alcohol concentration at suitable intervals, but in this case we cannot decide in which organ the metabolism takes place. Extra-hepatic metabolism may play a more important role at high than at low ethanol concentrations. The obvious solution to this problem is to measure the products formed from ethanol, not the disappearance of the substrate.