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-5- Problems of Alcohol on April 5, 1955. Reference numbers are included to indi- cate results which have already been published. All other comments not sup- ported by published articles should be considered as personal communications, not to be utilized for publication reference without the expressed permission of the investigator in question. II. THE METABOLISM OF ALCOHOL* Following the taking of an alcoholic solution into the stomach the alco- hol is absorbed from the stomach and amall intestine at a rate influenced by the presence of food in the stomach and a variety of other factors. (11) This variability has been at least one factor which has caused different results to be obtained from similar experiments studying the effects of alcohol on the organism. Once in the body, alcohol is almost certainly metabolized first to acet- aldehyde, although the exact enzyme or enzymes causing this change are not known with certainty. In almost all animals, including man, with the notable exception of the dog, acetaldehyde is found in the blcod stream in small amounts after alcohol has been ingested. The fact that the dog is different in this respect high- lights another problem which confronts those working in this field. Differ- ent species show significant variations in the way they handle alcohol, so that experimental findings derived from studies of a single species cannot be applied to man indiscriminately. (19) In any event, the metabolism of alcohol to acetaldehyde is an interest- ing process posing several unsolved problems. First, ethyl alcohol is burned by the body at an almost steady rate, ap- proximating 100 mg. per Kg. per hour in man, or about one pint of 100-proof liquor per day, (17) regardless of the concentration of alcohol in the blood. Almost all other substances metabolized by the body are metabolized much faster at high concentrations than at low ones, This implies that there may be in the body only a limited amount of the enzyme or enzymes which change alcohol to acetaldehyde; this small amount could act as a limiting factor, keeping the rate of alcohol metabolism down at its observed constant level. The situation becomes still more complicated. Some animals (especially dogs) will start out with a somewhat higher rate of alcohol metabolism if they are given a large dose of alcohol to start with than if they are given a small one, (45) But in either case the rate at which they burn alcohol when their blood concentration is highest remains constant as they metabolize the whole d»se they were given. It is possible that some of these animals are not burning alcohol to the best of their ability initially and that the *For more detailed review articles on the metabolism of ethyl alcohol, the interested reader is referred to the excellent review articles by Jacobsen (19) and Westerfeld (45) as well as Goodman and Gillman's textbook of pharmacology (10).
larger dose of alcohol may produce secondary effects, perhaps through stimu- lation of the adrenal glands or changes in liver function, which enable the body to increase its alcohol metabolism to its full capacity. In other spe- cies (and in some individual dogs) the rate of metabolism seems to be constant and unaffected by either the size of the dose or by the giving of hormones or other substances to the animal. In some animals the rate of metabolism of alcohol will deviate a little from the constant rate described above, making people suspect that two dif- ferent enzymes may perhaps be involved. There are two known enzymes, catalase and alcohol dehydrogenase, which can convert alcohol to acetaldehyde in the test tube. In many ways alcohol dehydrogenase would appear to be the enzyme primarily involved; it has been calculated to be present in the liver (of the horse) in amounts just proper to account for the limited rate of alcohol metabolism described above. To allow this reaction to occur, diphosphopyridine nucleotide, a molecule contain- ing the vitamin nicotinic acid, must be present; but for unknown reasons, the effects of nicotinic acid deficiency on alcohol metabolism have not yet been specifically investigated. (19) The other enzyme, catalase, if it were the only enzyme responsible, would cause a quite different relative rate of alcohol metabolism than that which is observed; but it is possible that it also metabolizes alcohol to a limited extent and may account for some of the unexplained deviations from the steady rate of alcohol metabolism sometimes found. . =. Dr. Kinard of the Medical College of South Carolina (aided by a grant . : from the Committee on Problems of Alcohol) has been studying the relation- .... ships between the rate at which the living dog metabolizes alcohol, the rate at which the dog's liver will metabolize alcohol in vitro after the dog has been sacrificed, and the amount of catalase activity present in the liver as . determined by a method not involving alcohol. His initial results in the living dog have indicated a positive relationship between the rate of alcohol metabolism and the catalase content of the liver, a finding at variance with the theoretical formulation presented above. He plans to expand these ob- servations and to attempt to alter the amounts of catalase and alcohol de- hydrogena.se in the liver by a variety of methods. His work should constitute a definite step toward the better understanding of the inter-relationships of these two enzymes. The next step in the metabolism of alcohol is the conversion of the acetaldehyde formed as described above, .perhaps by way of acetic acid, to acetyl coenzyme A (CoA). From the acetyi CoA stage the metabolism of the molecule to carbon dioxide and water is in no way different from the end steps in the metabolism of fat or carbohydrate, and so ceases to be of spe- cial concern to those interested in alcohol or alcoholism, The metabolism of acetaldehyde, however, is of considerable importance. . for at least three reasons. First, acetaldehyde is itself a substance with potent pharmacological effects. It has a narcotic action on the central ner- vous system and is a much more poisonous substance than alcohol, the fatal
blood level of acetaldehyde being less than one-eighth the fatal blood level of alcohol. Some of the effects of intoxication, as well as the hangover itself, have been blamed on acetaldehyde, but without proof. The levels normally present in the blood of an intoxicated person or animal are not high enough in themselves to produce the symptoms of intoxication. .'⢠Secondly, the fact that acetaldehyde is found in the blood at all is in itself a mystery, since liver slices,or homogenates in the laboratory metabo- lize acetaldehyde at a much faster rate than it could possibly be produced from the limited amount of alcohol the liâ¢tfer can metabolize .in a given unit of time. Thirdly, the metabolism of acetaldehyde in the body is interfered with by Antabuse (disulfiram), the violent nausea and flushing the patient experi- ences in the alcohol-Antabuse reaction being caused by the accumulation of unmetabolized acetaldehyde in his blood. The enzyme or enzymes metabolizing acetaldehyde are also unclear. Six enzymes capable of this function (in vitro) are known to exist in the body. Three ,of these are found in muscle in considerable quantities. Since in actuality living muscle barely⢠metabolizes acetaldehyde at all, it seems un- likely that these enzymes play any important role in the metabolism of acet- aldehyde by the living animal. The three others are all present in the liver, which is the primary site of acetaldehyde metabolism, and are called, re- spectively, xanthine oxidase, aldehyde pxidase and aldehyde dehydrogenase (or mutase). The enzyme actually metabolizing acetaldehyde must be inhibited by anta- buse in low concentrations. This condition rules out xanthine oxidase to start with. Both of the other known enzymes are inhibited by antabuse in this way, but cause acetaldehyde to be converted to acetic acid in the test tube. Since acetic acid is not formed in the living animal in measurable amounts by the metabolism of acetaldehyde, it is suspected either that the acetic acid itself.is metabolized very rapidly by the body or that acetalde- hyde is converted directly to acetyl CoA without acetic acid ever being formed. The latter theory would imply the existence of another enzyme, as yet undiscovered. Under a grant frort the Committee on Problems of Alcohol, Dr. Hulpieu of the Indiana University Medical Center has been working with animal (bone) charcoal, a substance which in moderate doses will produce an antabuse-like reaction to alcohol in both dogs and men. In a clinical trial he has found the symptoms produced by the two substances to be essentially identical. However, antabuse could not be isolated from animal charcoal, nor could any substance with .an antabuse-like action be extracted from the charcoal by any of a variety of procedures. The active principle in animal charcoal there- fore still remains a mystery. . â¢. Only two vitamins appear to be directly concerned in the metabolism of alcohol, nieotinic acid as mentioned above, and riboflavin in the conversion of acetaldehyde to acetic acid. There has been a surprising dearth of studies
