Charles S. Lieber

After consuming comparable amounts of ethanol, women have higher blood ethanol concentrations than men, even with allowance for differences in size, and are more susceptible to alcoholic liver disease. Recently, we documented significant "first-pass metabolism" of ethanol due to its oxidation by gastric tissue. We report a study of the possible contribution of this metabolism to the sex-related difference in blood alcohol concentrations in 20 men and 23 women. Six in each group were alcoholics. The first-pass metabolism was determined on the basis of the difference in areas under the curves of blood alcohol concentrations after intravenous and oral administration of ethanol (0.3 g per kilogram of body weight). Alcohol dehydrogenase activity was also measured in endoscopic gastric biopsies. In nonalcoholic subjects, the first-pass metabolism and gastric alcohol dehydrogenase activity of the women were 23 and 59 percent, respectively, of those in the men, and there was a significant correlation (rs = 0.659) between first-pass metabolism and gastric mucosal alcohol dehydrogenase activity. In the alcoholic men, the first-pass metabolism and gastric alcohol dehydrogenase activity were about half those in the nonalcoholic men; in the alcoholic women, the gastric mucosal alcohol dehydrogenase activity was even lower than in the alcoholic men, and first-pass metabolism was virtually abolished. We conclude that the increased bioavailability of ethanol resulting from decreased gastric oxidation of ethanol may contribute to the enhanced vulnerability of women to acute and chronic complications of alcoholism.

A hepatic microsomal ethanol-oxidizing system is described both in men and rats. It is distinguished from alcohol dehydrogenase by its subcellular localization (cytosol for alcohol dehydrogenase, microsomes for this system), its pH optimum (physiological pH versus pH 10 to 11 for alcohol dehydrogenase), and its cofactor requirements (NADPH versus NAD+ for alcohol dehydrogenase). It also requires oxygen and is inhibited by CO, properties commonly found among microsomal drug-detoxifying enzymes. That catalase is probably not involved was revealed by the partial or complete failure of cyanide, pyrazole, azide, or 3-amino-1,2,4-triazole to inhibit the NADPH-dependent microsomal ethanol-oxidizing system under conditions which diminished catalase activity. Moreover, a combination of administration in vivo of pyrazole and addition in vitro of azide virtually blocked catalase activity and abolished 95% of a H2O2-dependent microsomal ethanol oxidation, whereas two-thirds of the activity of the NADPH-dependent ethanol oxidation persisted. Ethanol feeding resulted in a striking rise of hepatic NADPH-dependent microsomal ethanol-oxidizing activity, whereas under the same conditions, activities of alcohol dehydrogenase in the cytosol and of microsomal as well as of total hepatic catalase did not increase. Furthermore, blood ethanol clearance was accelerated, which suggests that microsomal ethanol oxidation may play a role in vivo. Pyrazole, which inhibits alcohol dehydrogenase strongly (affecting also other hepatic functions, including microsomal enzymes) markedly reduced but did not block ethanol metabolism in vivo or in liver slices. Even after pyrazole, ethanol clearance rates remained significantly higher in ethanol-pretreated rats. The existence of a microsomal ethanol-oxidizing system, especially its capacity to increase in activity adaptively after ethanol feeding, may explain various effects of ethanol, including proliferation of hepatic smooth endoplasmic reticulum, induction of other hepatic microsomal drug-detoxifying enzymes, and the metabolic tolerance to ethanol which develops in alcoholics.

The technique of feeding ethanol as part of a totally liquid diet was invented two decades ago and its successful application for the intervening period is reviewed. This technique results in much higher ethanol intake than with conventional procedures. As a consequence, various complications observed in alcoholics were reproduced in animal models, including fatty liver, hyperlipemia, various metabolic and endocrine disorders, tolerance to ethanol and other drugs, physical dependence and withdrawal, the fetal alcohol syndrome and, in the baboon, liver fibrosis and cirrhosis. Variations of the liquid diet formulation are compared and three standardized basic formulas are being proposed for the rat: (1) a regular diet, comparable to the diet previously referred to as the "Lieber-DeCarli Formula" and suitable for most experimental applications, particularly those intended to mimic the clinical situation in which the various effects of alcohol occur in the setting of liver changes characterized by a fatty liver; (2) a low fat diet comparable in all respects to the preceding diet but with a lower fat content, intended to minimize the hepatic changes; and (3) a high protein formula particularly useful in those circumstances in which an oversupply of dietary protein might be recommended (i.e., pregnancy and lactation).