Fatty acid ethyl esters and heart disease

Puran S. Bora

Crdiomyopathy refers to a family of diseases characterized by the inability of heart muscles to contract normally. This disorder, which is the result of processes affecting cardiac muscle cells, diminishes the pumping capacity of the heart and results in abnormal rhythms and congestive heart failure. Unlike other cardiac maladies, cardiomyopathy does not involve the coronary arteries and cardiac valves. At least 1 million people in the United States suffer from cardiomyopathy.

Researchers have implicated alcohol abuse in the onset of certain cardiomyopathies, especially in a large percentage of cases occurring in developed countries (see the article by Rubin and Doria, pp. 277-284). These cases are referred to collectively as alcohol-induced hearft muscle disease. They often are diagnosed by excluding other cardiomyopathies and by documenting significant and prolonged consumption of falcohol by the patient.

Attempts to elucidate the causes of alcohol-induced heart muscle disease historically have been hampered by the lack of evidence of metabolic, or chemical, activity of alcohol in heart tissues. However, scientists recently have demonstrated that cardiac muscle does metabolize alcohol, and they have found that it produces a family of molecules known as fatty acid ethyl esters (Mogelson and Lange 1984; Laposata and Lange 1986; Bora et al. 1989b; Laposata et al. 1989; Bora and Lange in press a, b). The formation of fatty acid ethyl esters in the heart is an example of a nonxidative metabolism of alcohol, and is distinguished from the oxidative metabolism of alcohol in the liver. Fatty acid ethyl esters may prove to be the first link between the ingestion of alcohol and the development of alcohol-induced heart muscle disease.

FATTY ACID ETHYL ESTERS

In general, alcohols react with organic acids to produce neutral molecules known as esters. The reaction of ethyl alcohol (ethanol) with fatty acids--weak organic acids that play functional roles in human cells--produces fatty acid ethyl esters (FAEEs). Although the amount of fatty acids in heart muscle is small, FAEEs formed by the reaction with alcohol can persist and accumulate in heart tissues for a time after alcohol consumption.

Under physiological conditions in the body, the total intracellular concentration of free fatty acids is 0.25 micromoles to 0.50 micromoles per gram. In comparison, the normal concentrtion of FAEEs in heart muscle is less than 0.001 micromoles per liter (Lange and Sobel 1983a). Following consumption of alcohol, FAEEs can accumulate in the human myocardium in concentrations as high as 115 micromoles per liter (Table 1; Lange and Sobel 1983b). An analysis of four subjects who were acutely intoxicated at the time of death detected FAEE concentrations in heart tissue of between 17 micromoles and 115 micromoles per liter (Table 1). Similar analysis detected FAEE concentrations of 9 micromoles and 28 micromoles per liter in the heart tissues of two subjects who were known to be chronic consumers of alcohol but who died at a time when their blood alcohol concentration was zero (last two subjects in Table 1). Because these two subjects had consumed alcohol within 48 hours prior to death, the data demonstrated that FAEEs can be detected in the myocardium for at least 24 to 48 hours after consumption.

The FAEEs that form in the heart after exposure to alcohol may damage the mitochondria of cells or impair their funciton. Mitochondria are cellular

TABLE 1 Concentrations of Fatty Acid Ethyl Esters (FAEE) (in Heart Tissue) and Alcohol (in Blood) for Six Subjects at the Time of Death

FAEE Concentration     Alcohol Concentration
[mu]mol/l     [mu]mol/g     mg/100 ml
115           0.092            43
 60           0.048           121
 28           0.023           283
 17           0.013           186
  9           0.007             0
 28           0.023             0
  Adapted from Lange and Sobel 1983b.

components essential for the production of energy. When mitochondria are isolated from heart tissue and incubated with FAEEs, thefre is a loss in the ability of the mitochondria to synthesize ATP, the molecule responsible for storing energy to be used in the cell (Lange and Sobel 1983a). This loss of oxidative funciton depends on the concentration of FAEEs and has been observed at concentrations that occur in the heart following consumption of alcohol (Lange and Sobel 1983a).

Free fatty acids, which are toxic to mitochondria, normally are bound to intracellular fatty acid binding sites, and are not available for reacting with mitochondria (Figure 1). However, in the presence of alcohol, fatty acids react to form FAEEs, which are neutral molecules, and bind or attach themselves less readily to protein molecules and instead can bind to and accumulate on the mitochondria (Figure 1). The mitochondria respond to the fatty acid ethyl esters by producing an enzyme that catalyzes the breakdown of the esters to alcohol and fatty acid (Lange and Sobel 1983a; Bora et al. 1989a). When enzymes react with FAEEs near the mitochondria to form toxic fatty acids, the functioning of the mitochondria is jeopardized. Impairment of mitochondrial activity means that energy production becomes less efficient, resulting in damage to cell functions that rely on the energy from the mitochondria.

The normal activity of the mitochondria therefore appears to be jeopardized by the presence of both fatty acids and FAEEs (Lange and Sobel 1983a). Harm to the mitochondria and cells might occur in a cumulative manner during several years of alcohol use, eventually reaching the point where the mitochondria and the cell cannot repair themselves.

Fatty acid ethyl esters also may inhibit the normal synthesis and secretion of protein in heart muscle cells, although further work is needed to confirm this. Mair and co-workers (1990) observed such an effect following chronic exposure of liver cells to fatty acid ethyl esters.

THE ROLE OF ENZYMES

Enzyme molecules catalyze chemical reactions, and in the human body, a specific enzyme usually will catalyze a particular reaction. The formation of FAEEs in the body is aided by an enzyme known as fatty acid ethyl ester synthase (Mogelson and Lange 1984; Mogelson et al. 1984; Lange 1982). This enzyme exists in three distinct forms in the human myocardium: Synthase I, Synthase II, and Synthase III (Bora et al. 1989a,b,c; Figure 2).

All three synthases catalyze the formation of fatty acid ethyl esters; however, Synthase I and Synthase III also catalyze the metabolsim of certain carcinogens, that is, they help to eliminate cancer-causing chemicals. Synthase I and Synthase III might also metabolize carcinogens in the heart. The effort by the synthases to metabolize both alcohol and carcinogens possibly might result in incomplete metabolism of either or both substances. Such an effect is perhaps revealed in the link between alcohol abuse and the propensity to develop tumors of the pharynx, esophagus, stomach, and liver--four organs which, in abusers, are exposed to high concentrations of alcohol (Engstrom 1977; Lieber et al. 1979).

REFERENCES

BORA, P.S., AND LANGE, L.G. Fatty acid ethyl ester, alcohol, and liver changes. In: Watson, R.R., ed. Alcohol and Drug Abuse Reviews: Liver Pathology and Drugs of Abuse. Vol. II. Clifton, NJ: Humana Press, in press a.

BORA, P.S., AND LANGE, L.G. Homogeneous Synthase I from human myocardium is a glutathione S-transferase. Annals of the New York Academy of Sciences, in press b.

BORA, P.S.; SPILBURG, C.A.; AND LANGE, L.G. Identification of a satellite fatty acid ethyl ester synthase from human myocardium as a glutathione S-transferase. Journal of Clinical Investigation 84(6):1942-1946, 1989a.

BORA, P.S.; SPILBURG, C.A.; AND LANGE, L.G. Metabolism of ethanol and carcinogens by glutathione transferases. Proceedings of the National Academy of Sciences, USA 86(12):4470-4473, 1989b.

BORA, P.S.; SPILBURG, C.A.; AND LANGE, L.G. Purification to homogeneity and characterization of major fatty acid ethyl ester synthase from human myocardium. FEBS Letters 258(2):236-239, 1989c.

ENGSTROM, J.E. Colonestal cancer and beer drinking. British Journal of Cancer Research 35:679-684, 1977.

LANGE, L.G. Nonoxidatie ethanol metabolism. Formation of fatty acid ethyl esters by cholesterol esterase. Proceedings of the National Academy of Sciences, USA 79(13):3954-3957, 1982.

LANGE, L.G., AND SOBEL, B.E. Mitochondrial dysfunction induced by fatty acid ethyl esters, myocardial metabolites of ethanol. Journal of Clinical Investigation 72(2):724-731, 1983a.

LANGE, L.G., AND SOBEL, B.E. Myocardial metabolities of ethanol. Circulation Research 52:479-482, 1983b.

LAPOSATA, E.A., AND LANGE, L.G. Presence of nonxidative ethanol metabolism in human organs commonly damaged by ethanol abuse. Since 231(4737):497-499, 1986.

LAPOSATA, E.A.; SCHERRER, D.E.; AND LANGE, L.G. Fatty acid ethyl esters in adipose tissue: A laboratory marker for alcohol-related death. Archives of Pathology and Laboratory Medicine 113(7):762-766, 1989.

LIEBER, C.S.; Seitz, H.K.; GARRO, A.J.; AND WORNER, T.M. Alcohol-related diseases and carinogenesis. Cancer Research 39:2863-2867, 1979.

MAIR, D.C.; DONNELL, M.E.; AND LAPOSATA, E.A. Fatty acid ethyl esters, a family of ethanol metabolites, mediate changes in protein secretion in HEP G2 cells. Clinical Research 38:264a, 1990.

MOGELSON, S., AND LANGE, L.G. Nonoxidative ethanol metabolism in rabbit myocardium: Purification to homogeneity of fatty acid acyl ethyl ester synthase. Biochemistry 23:4075-4081, 1984.

MOGELSON, S.; PIEPER, S.J.; AND LANGE, L.G. Thermodynamic bases for fatty acid ethyl ester synthase catelyzed esterification of free fatty acid with esthanol and accumulation of fatty acid ethyl esters. Biochemistry 23:4082-4087, 1984.

PURAN S. BORA, PH.D., is assistant professor of medicine and of psychiatry, Washington University School of Medicine, St. Louis, Missouri, and Jewish Hospital of St. Louis.

LOUIS G. LANGE, M.D., PH.D., is professor of medicine, pathology, and psychiatry, Washington University School of Medicine, St. Louis, Missouri, and is chief of cardiovascular diseases, Jewish Hospital of St. Louis.

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